Pharmaceutical formulations and methods for the treatment of gastrointestinal disorders

ABSTRACT

Provided herein is a bulk composition comprising the trihydrate form of (3S, 4R, 3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. Provided are also pharmaceutical compositions and dosage forms comprising the trihydrate form, and methods and uses for treating a gastrointestinal disorder in a subject with the trihydrate form. In some embodiments, the gastrointestinal disorder is gastroesophageal reflux disease (GERD), dyspepsia (such as functional dyspepsia or functional motility disorder), gastroparesis, paralytic ileus, post-operative ileus, emesis, nausea, heartburn, intestinal pseudo-obstruction, irritable bowel syndrome (IBS), constipation, enteral feeding intolerance (EFI), or esophagitis. In some embodiments, the gastrointestinal disorder is post-operative ileus, chronic grass sickness, constipation, megacolon, gastritis, gastrointestinal stasis, or abomasal emptying defect.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 18/157,783, filed Jan. 20, 2023, which is a divisional applicationof U.S. application Ser. No. 17/887,325, filed Aug. 12, 2022, now U.S.Pat. No. 11,643,409, which is a continuation application of U.S.application Ser. No. 16/734,961, filed Jan. 6, 2020, now U.S. Pat. No.11,498,918, which is a divisional application of U.S. application Ser.No. 16/181,177, filed Nov. 5, 2018, now U.S. Pat. No. 10,570,127, eachof which is hereby incorporated by reference in its entirety.

FIELD

The present disclosure relates to bulk compositions and pharmaceuticalcompositions comprising a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, andmethods of treating gastrointestinal disorders with this form.

BACKGROUND

Benzamide derivatives and pharmaceutically acceptable salts thereof canact as stimulators of gastrointestinal motility. Many of these compoundsare also antagonists of the dopamine D2 receptor, which also plays animportant role in the gastrointestinal system. Dopaminergic effects inthe gastrointestinal system may include nausea and vomiting. Thus, someof these benzamides are effective anti-emetic agents and they may beused to control vomiting during cancer chemotherapy or radiotherapy,especially when highly emetogenic compounds such as cisplatin are used.This anti--emetic action is believed to be the result of the ability ofthe benzamides to block the actions of serotonin (5HT) at specific sitesof action, called the 5HT₃-receptor.

A second prominent action of some benzamide, derivatives is inaugmenting gastrointestinal smooth muscle activity from the esophagusthrough the proximal small bowel, thus accelerating esophageal and smallintestinal transit as well as facilitating gastric emptying andincreasing lower esophageal sphincter tone. It is currently believedthat the primary smooth muscle effects of some benzamide derivatives arethe result of an agonist action upon a class of serotonin receptorsreferred to as 5HT₄ receptors, which are :located on interneurons in themyenteric plexus of the gut wall.

The benzamide Cisapride, a potent 5-HT₄ agonist, was introduced morethan 20 years ago and it has been used primarily to treatgastroesophageal reflux disease (GERD). Other 5-HT₄ agonists of thebenzamide class were subsequently introduced to patients. Because oftheir activity as prokinetic agents, some 5-HT₄ agonists also appear tobe useful to treat dyspepsia, gastroparesis, constipation,post-operative ileus, and intestinal pseudo-obstruction.

However, many of these compounds, including Cisapride, are associatedwith serious cardiac arrhythmias, such as ventricular tachycardia,ventricular fibrillation, torsades de pointer, and QT prolongation. Thesafety of 5HT₄ receptor agonists may also be limited by adverse druginteractions due to hepatic cytochrome P-450 metabolism. Thus, what isneeded in the art are benzamide 5-HT₄ agonists that have a lowerincidence of cardiac arrhythmias, which may be used to treatgastrointestinal disorders.

Naronapride ((3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt) is anorally bioavailable selective serotonin 5-HT4 receptor agonist that hasbeen shown in animals and in humans to be safe for use in treatinggastrointestinal disorders, and has a low incidence of adversecardiovascular effects. See U.S. Pat. Nos. 7,176,218; 7,282,509;7,326,787; 7,629,466; 8,138,204; and 8,524,736 incorporated herein byreference in their entireties. What is needed in the art are improvedforms of naronapride for clinical use, and methods of producing bulkcompositions thereof.

BRIEF SUMMARY

In some aspects, provided herein is a bulk composition comprising atrihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, which hasthe following formula:

and at least one container.

In other aspects, provided herein is a pharmaceutical compositioncomprising a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, which hasthe following formula:

-   -   and a pharmaceutically acceptable excipient.

In certain aspects, provided herein is a dosage form that includes thepharmaceutical composition.

Also provided herein is a method of treating a gastrointestinal disorderin a subject in need thereof, which includes administering to thesubject in need thereof a therapeutically effective amount of apharmaceutical composition provided herein, or a dosage form providedherein, comprising the trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. In someembodiments, the gastrointestinal disorder is selected from the groupconsisting of gastroesophageal reflux disease (GERD), functionaldyspepsia or functional motility disorder, gastroparesis, paralyticileus, post-operative ileus, emesis, nausea, heartburn, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis. In some embodiments,the subject in need thereof is a human. In other embodiments, thegastrointestinal disorder is selected from the group consisting ofpost-operative ileus, chronic grass sickness, constipation, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect. Insome embodiments, the subject in need thereof is a non-human animal,such as a ruminant, an equine, a cat, a dog, a rabbit, or a guinea pig.

In other embodiments, provided herein is the use of a trihydrate form of(3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt in themanufacture of a medicament for treating a gastrointestinal disorder ina subject in need thereof. In some embodiments, the gastrointestinaldisorder is selected from the group consisting of gastroesophagealreflux disease (GERD), functional dyspepsia or functional motilitydisorder, gastroparesis, paralytic ileus, post-operative ileus, emesis,nausea, heartburn, intestinal pseudo-obstruction, irritable bowelsyndrome (IBS), constipation, enteral feeding intolerance (EFI), andesophagitis. In some embodiments, the subject in need thereof is ahuman. In other embodiments, the gastrointestinal disorder is selectedfrom the group consisting of post-operative ileus, chronic grasssickness, constipation, megacolon, gastritis, gastrointestinal stasis,and abomasal emptying defect. In some embodiments, the subject in needthereof is a non-human animal, such as a ruminant, an equine, a cat, adog, a rabbit, or a guinea pig.

In still other aspects, provided herein is a compound, or pharmaceuticalcomposition comprising a compound, for use in treating agastrointestinal disorder in a subject in need thereof, wherein thecompound is a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. In someembodiments, the gastrointestinal disorder is selected from the groupconsisting of gastroesophageal reflux disease (GERD), functionaldyspepsia or functional motility disorder, gastroparesis, paralyticileus, post-operative ileus, emesis, nausea, heartburn, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis. In some embodiments,the subject in need thereof is a human. In other embodiments, thegastrointestinal disorder is selected from the group consisting ofpost-operative ileus, chronic grass sickness, constipation, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect. Insome embodiments, the subject in need thereof is a non-human animal,such as a ruminant, an equine, a cat, a dog, a rabbit, or a guinea pig.

In other aspects, provided herein is a method of improvinggastrointestinal motility in a subject in need thereof, which includesadministering to the subject in need thereof a therapeutically effectiveamount of a pharmaceutical composition provided herein, or a dosage formprovided herein, comprising the trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. In someembodiments, the subject in need thereof has a gastrointestinaldisorder. In some embodiments, the gastrointestinal disorder is selectedfrom the group consisting of gastroesophageal reflux disease (GERD),functional dyspepsia or functional motility disorder, gastroparesis,paralytic ileus, post-operative ileus, emesis, nausea, heartburn,intestinal pseudo-obstruction, irritable bowel syndrome (IBS),constipation, enteral feeding intolerance (EFI), and esophagitis. Insome embodiments, the subject in need thereof is a human. In otherembodiments, the gastrointestinal disorder is selected from the groupconsisting of post-operative ileus, chronic grass sickness,constipation, megacolon, gastritis, gastrointestinal stasis, andabomasal emptying defect. In some embodiments, the subject in needthereof is a non-human animal, such as a ruminant, an equine, a cat, adog, a rabbit, or a guinea pig.

In other embodiments, provided herein is the use of a trihydrate form of(3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt in themanufacture of a medicament for improving gastrointestinal motility in asubject in need thereof. In some embodiments, the subject in needthereof has a gastrointestinal disorder selected from the groupconsisting of gastroesophageal reflux disease (GERD), functionaldyspepsia or functional motility disorder, gastroparesis, paralyticileus, post-operative ileus, emesis, nausea, heartburn, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis. In some embodiments,the subject in need thereof is a human. In other embodiments, thegastrointestinal disorder is selected from the group consisting ofpost-operative ileus, chronic grass sickness, constipation, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect. Insome embodiments, the subject in need thereof is a non-human animal,such as a ruminant, an equine, a cat, a dog, a rabbit, or a guinea pig.

In still other aspects, provided herein is a compound, or pharmaceuticalcomposition comprising a compound, for use in improving gastrointestinalmotility in a subject in need thereof, wherein the compound is atrihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. In someembodiments, the subject in need thereof has a gastrointestinaldisorder. In some embodiments, the gastrointestinal disorder is selectedfrom the group consisting of gastroesophageal reflux disease (GERD),functional dyspepsia or functional motility disorder, gastroparesis,paralytic ileus, post-operative ileus, emesis, nausea, heartburn,intestinal pseudo-obstruction, irritable bowel syndrome (IBS),constipation, enteral feeding intolerance (EFI), and esophagitis. Insome embodiments, the subject in need thereof is a human. In otherembodiments, the gastrointestinal disorder is selected from the groupconsisting of post-operative ileus, chronic grass sickness,constipation, megacolon, gastritis, gastrointestinal stasis, andabomasal emptying defect. In some embodiments, the subject in needthereof is a non-human animal, such as a ruminant, an equine, a cat, adog, a rabbit, or a guinea pig.

DESCRIPTION OF THE FIGURES

FIG. 1 is a water vapor sorption isotherm of the di-hydrochloride saltat 25° C. (two left lines) and 50° C. (two right lines).

FIG. 2 are Fourier transform infrared (FTIR) spectra of the anhydrateand the trihydrate forms of the (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

FIG. 3 are X-ray powder diffraction (XRPD) patterns of the anhydrate(bottom) and the trihydrate (top) forms of the (3S, 4R,3′R)-6-[4-(4-amino-5-ehloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

FIG. 4 is a water vapor sorption isotherm of the di-hydrochloride saltat 25° C.

FIG. 5 provides thermographic analysis scans for the anhydrate (topline) and trihydrate (bottom line) forms.

FIG. 6 is a representative ¹H-NMR spectrum of the trihydrate form.

FIG. 7 is a representative ¹³C-NMR spectrum of the trihydrate form.

DETAILED DESCRIPTION

Provided herein is a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt (Compound1), which has the following formula:

Also provided herein are bulk compositions comprising Compound 1, and acontainer. In other aspects, provided herein is a pharmaceuticalcomposition comprising Compound 1 and a pharmaceutically acceptableexcipient. Further provided herein are methods of treating a disorder ina subject in need thereof, comprising administering to the subject inneed thereof a therapeutically effective amount of Compound 1, or apharmaceutical composition comprising a therapeutically effective amountof Compound 1; and the use of Compound 1, or a pharmaceuticalcomposition comprising Compound 1, in treating a disorder in a subjectin need thereof; and the use of Compound 1 in the manufacture of amedicament for treating a disorder in a subject in need thereof.

I. COMPOUND 1

It has been surprisingly found that the di-hydrochloride salt of (3S,4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester can exist in a trihydrate form.The trihydrate form (Compound 1) has many advantages over the anhydrousform, including tolerance of a broader range of storage conditions andthe ability to be formulated with hydrated and/or hygroscopicexcipients. The difference in formula weights between the anhydrous form(FW=610.01 g/mol) and the trihydrate (FW=664.06 g/mol) would result inan approximately 8% to 9% deficit in a final formulation if the wrongform is used (e.g., using the trihydrate when the anhydrous is intended,or the anhydrous when the trihydrate is intended). Thus, provided hereinare also X-ray powder diffraction peaks which may, in some embodiments,be used to identify which form is present in a composition.

A. X-Ray Powder Diffraction (XRPD)

In some embodiments, Compound 1 (including the Compound 1 in the bulkcompositions, pharmaceutical compositions, dosage forms, kits, ormedicaments comprising any of these as provided herein) is in acrystalline form, and the crystalline form has XRPD 2-theta (2θ) peaksat: 7.74°±0.5° (>50% relative intensity), and 20.95°±0.5° (100% relativeintensity). In some embodiments, Compound 1 has XRPD 2-theta (2θ) peaksat: 7.6°±0.2° (>50% relative intensity), and 20.7°±0.2° (100% relativeintensity). In other embodiments, Compound 1 is in an amorphous form.

In some embodiments, Compound 1 is in a crystalline form, and thecrystalline form has XRPD peaks at (degrees 2-theta (2θ)) 7.74°±0.5°,and 20.95°±0.5°, and at least one, at least two, at least three, atleast four, at least five, at least six, at least seven, at least eight,at least nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, at least twenty,or each of the XRPD 2-theta (2θ) peaks selected from the groupconsisting of 10.3°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.0°±0.2°,15.4°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.3°±0.2°,22.0°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 27.2°±0.2°,30.1°±0.2°, 32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°, and 39.4°±0.2°.

In some embodiments, Compound 1 is in a crystalline form, and thecrystalline form has XRPD 2-theta (2θ) peaks at 7.6°±0.2°, 10.3°±0.2°,and 20.7°±0.2°. In certain embodiments, Compound 1 is in a crystallineform, and the crystalline form has XRPD 2-theta (2θ) peaks at 7.6°±0.2°,10.3°±0.2°, 19.2°±0.2°, and 20.7°±0.2°. In other embodiments, Compound 1is in a crystalline form, and the crystalline form has XRPD 2-theta (2θ)peaks at 7.6°±0.2°, 10.3°±0.2°, 19.2°±0.2°, 20.7°±0.2°, and 33.4°±0.2°.In still further embodiments, Compound 1 is in a crystalline form, andthe crystalline form has XRPD 2-theta (2θ) peaks at 7.6°±0.2°,10.3°±0.2°, 19.2°±0.2°, 20.7°±0.2°, 33.4°±0.2°, and 38.2°±0.2°. In someembodiments, Compound 1 is in a crystalline form, and the crystallineform has XRPD 2-theta (2θ) peaks at 7.6°±0.2°, 10.3°±0.2°, 13.6°±0.2°,19.°±0.2°, 20.7°±0.2°, 33.4°±0.2°, and 38.2°±0.2°. In furtherembodiments, Compound 1 is in a crystalline form, and the crystallineform has XRPD 2-theta (2θ) peaks at 7.6°±0.2°, 10.3°±0.2°, 13.6°±0.2°,19.2°±0.2°, 20.7°±0.2°, 30.1°±0.2°, 33.4°±0.2°, and 38.2°±0.2°. Incertain embodiments, Compound 1 is in a crystalline form, and thecrystalline form has XRPD 2-theta (2θ) peaks at 7.6°±0.2°, 10.3°±0.2°,13.6°±0.2°, 19.2°±0.2°, 20.7°±0.2°, 26.0°±0.2°, 30.1°±0.2°, 33.4°±0.2°,and 38.2°±0.2°. In still further embodiments, Compound 1 is in acrystalline form, and the crystalline form has at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, at least twenty,at least twenty one, at least twenty two, or each of the XRPD 2-theta(2θ) peaks selected from the group consisting of 7.6°±0.2°, 10.3°±0.2°,13.6°±0.2°, 14.8°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 17.5°±0.2°, 18.3°±0.2°,18.6°±0.2°, 19.2°±0.2°, 20.7°±0.2°, 21.3°±0.2°, 22.0°±0.2°, 23.6°±0.2°,24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 27.2°±0.2°, 30.1°±0.2°, 32.4°±0.2°,33.4°±0.2°, 38.2°±0.2°, and 39.4°±0.2°. In some embodiments, thecrystalline form of Compound 1 has at least three of these peaks. Inother embodiments, the crystalline form of Compound 1 has at least fourof these peaks. In other embodiments, the crystalline form of Compound 1has at least five of these peaks. In other embodiments, the crystallineform of Compound 1 has at least six of these peaks. In otherembodiments, the crystalline form of Compound 1 has at least seven ofthese peaks. In other embodiments, the crystalline form of Compound 1has at least eight of these peaks. In other embodiments, the crystallineform of Compound 1 has at least nine of these peaks. In otherembodiments, the crystalline form of Compound 1 has at least ten ofthese peaks. In certain embodiments, for a crystalline form of Compound1 with XRPD 2-theta (2θ) peaks at 7.6°±0.2° and 20.7°±0.2° (including,for example, a crystalline form with three, four, five, six, seven,eight or more XRPD peaks as described herein), the peak at 7.6°±0.2° hasgreater than 50% relative intensity, and the peak at 20.7°±0.2° has 100%relative intensity.

B. Bulk Compositions

In some embodiments, provided herein are bulk compositions comprisingCompound 1. Bulk compositions may include, for example, compositionscomprising at least 1 kg of Compound 1, at least 10 kg of Compound 1, atleast 50 kg of Compound 1, at least 100 kg of Compound 1, at least 150kg of Compound 1, at least 200 kg of Compound 1, at least 250 kg ofCompound 1, at least 300 kg of Compound 1, at least 350 kg of Compound1, at least 400 kg of Compound 1, at least 450 kg of Compound 1, or atleast 500 kg of Compound 1. In some embodiments, the bulk compositioncomprises between about 50 kg to about 500 kg of Compound 1, betweenabout 100 kg to about 400 kg of Compound 1, between about 100 kg toabout 300 kg of Compound 1, between about 150 kg to about 250 kg ofCompound 1, between about 200 kg to about 350 kg of Compound 1, orbetween about 200 kg to about 300 kg of Compound 1.

In further embodiments, provided herein are bulk compositions comprisingCompound 1 and at least one container. Any suitable container may beused. For example, in some embodiments, the container is a box, abucket, a barrel, a bottle, a jar, a bag, a crate, a pail, a tray, or atarp. In some embodiments, the bulk composition comprises Compound 1 andtwo or more containers, such as three containers, four containers, fivecontainers, or greater than five containers. In bulk compositionscomprising two or more containers, in some embodiments each of the twoor more containers are the same type, for example they are each abarrel, each a pail, each a box, etc. In other embodiments of bulkcompositions comprising two or more containers, at least two containersare of different types. In certain embodiments, the bulk compositioncomprises Compound 1 and at least one container, wherein each containeris independently selected from the group consisting of a box, a bucket,a barrel, a bottle, a jar, a bag, a crate, a pail, a tray, and a tarp.In certain embodiments, the container comprises a lid, for example ascrew-top lid or a lid that snaps on. In some embodiments, the lid isdetachable, while in other embodiments it is attached, for example by atether. The container may comprise any suitable material, or combinationof materials. For example, in some embodiments the container comprisesglass, metal, plastic, cardboard, wood, or any combinations thereof. Inembodiments in which the bulk composition comprises two or morecontainers, in some embodiments each container comprises the samematerial, while in other embodiments at least two of the containerscomprise different materials. In some embodiments, the one or morecontainers of the bulk composition are free of contaminants. Forexample, in some embodiments the one or more containers are suitable foruse in storing an active pharmaceutical ingredient (API) intended foradministration to a mammal, such as a human.

In some embodiments, at least a portion of the Compound 1 of the bulkcomposition is inside one or more containers. In certain embodiments, atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 95%, atleast 99% of the bulk composition is located within one or morecontainers. In some embodiments, provided herein is a bulk compositioncomprising Compound 1 and two or more containers, wherein each containercontains at least a portion of the Compound 1. In certain embodiments,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 95%, atleast 99% of Compound 1, in total, is located within the two or morecontainers. At least a portion of Compound 1 of the bulk compositionmay, in some embodiments, be evenly distributed between the two or morecontainers, or in other embodiments may be unevenly distributed.

In some embodiments, the bulk composition comprises at least 50% byweight, at least 55% by weight, at least 60% by weight, at least 65% byweight, at least 70% by weight, at least 75% by weight, at least 80% byweight, at least 85% by weight, at least 90% by weight, at least 95% byweight, at least 96% by weight, at least 97% by weight, at least 98% byweight, at least 99% by weight, or at least 99.9% by weight of Compound1, wherein the weight % excludes the weight of the container. In certainembodiments, the bulk composition comprises at least 75% by weight ofCompound 1, excluding the weight of the container.

In some embodiments, the bulk composition comprises less than about 6000ppm of organic solvent. In some embodiments, the bulk compositioncomprises less than about 5500 ppm, less than about 5000 ppm, less thanabout 4500 ppm, less than about 4000 ppm, less than about 3500 ppm, lessthan about 3000 ppm, less than about 2500 ppm, or less than about 2000ppm organic solvent. In some embodiments, the organic solvent comprisesone or more alcohols. In some embodiments, the organic solvent comprisesone or more C₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. In certain embodiments,the organic solvent comprises isopropanol, n-propanol, ethanol, ormethanol, or any combinations thereof. In some embodiments, the organicsolvent comprises isopropanol.

C. Pharmaceutical Compositions, Dosage Forms, and Kits

Also provided herein are pharmaceutical compositions comprising Compound1 and a pharmaceutically acceptable excipient. Pharmaceuticallyacceptable excipients may include, for example, an adjuvant, carrier,glidant, sweetening agent, diluent, preservative, dye/colorant, flavorenhancer, surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

In some embodiments, the pharmaceutical composition is a solid. Forexample, in some embodiments, the pharmaceutical composition is apowder, or a tablet. In certain embodiments, the pharmaceuticalcomposition is combined with a suitable medium to produce a liquid, andthe liquid is administered to a subject in need thereof. In someembodiments, the liquid is administered parenterally (for example,intravenously). In other embodiments, the liquid is administeredenterally, such as through a gastrointestinal tube (for example orallyor rectally through a gastrointestinal tube). In some embodiments, theliquid is administered orally, such as with a syringe, cup, or spoon. Insome embodiments, the suitable medium is aqueous.

Further provided herein are dosage forms comprising a pharmaceuticalcomposition as described herein. In some embodiments, the dosage formcomprises one or more tablets, or one or more capsules. In someembodiments, the dosage form is a powder in a sealed vial, which iscombined with a suitable medium before being administered. In someembodiments, the suitable medium is aqueous.

In yet still further embodiments, provided herein are kits comprising adosage form as described herein, and packaging. Any suitable packagingmay be used. In some embodiments, the packaging comprises a bottle, or ablister pack, or a vial. In some embodiments, the kit comprises a dosageform, wherein the dosage form comprises one or more tablets or one ormore capsules, and packaging, wherein the packaging is a blister pack.The blister pack, in some embodiments, is sealed with a plastic film, ora foil film, or a film comprising plastic and foil. In some embodiments,the kit comprises a suitable medium to be mixed with the dosage formprior to administration to the subject in need thereof. For example, insome embodiments the kit comprises a dosage form as a powder in a sealedvial, and an aqueous medium in a separate container (such as a vial, orsyringe, or bottle), and the dosage form is combined with the aqueousmedium before being administered to the subject in need thereof (forexample, orally).

In some embodiments, the pharmaceutical composition, dosage form, or kitcomprises less than about 6000 ppm of organic solvent. In someembodiments, the pharmaceutical composition, dosage form, or kitcomprises less than about 5500 ppm, less than about 5000 ppm, less thanabout 4500 ppm, less than about 4000 ppm, less than about 3500 ppm, lessthan about 3000 ppm, less than about 2500 ppm, or less than about 2000ppm organic solvent. In some embodiments, the organic solvent comprisesone or more alcohols. In some embodiments, the organic solvent comprisesone or more C₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. In certain embodiments,the organic solvent comprises isopropanol, n-propanol, ethanol, ormethanol, or any combinations thereof. In some embodiments, the organicsolvent comprises isopropanol.

D. Water Content and Ratios

In certain embodiments, the bulk composition, pharmaceuticalcomposition, dosage form, kit, or medicament comprises at least about5.0%, at least about 5.5%, at least about 6.0%, at least about 6.5%, atleast about 7.0%, at least about 7.5%, at least about 8.0%, at leastabout 8.5%, at least about 9.0%, at least about 9.5%, at least about10.0%, at least about 10.5%, at least about 11.0%, at least about 11.5%,or at least about 12.0% by weight water relative to the total weight of(3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt present inanhydrous or trihydrate form. In some embodiments, the bulk composition,pharmaceutical composition, dosage form, kit, or medicament comprisesbetween about 6.5% by weight to about 10% by weight, or between about7.5% by weight to about 9.0% by weight, or about 8.5% by weight water,relative to the total weight of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt present inthe trihydrate form, and (if present) the anhydrous form. In someembodiments, only the trihydrate form is present. In certainembodiments, the anhydrous form is also present, and the water contentis evaluated relative to the total weight of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt in boththe trihydrate and the anhydrous forms. In some embodiments, the bulkcomposition, pharmaceutical composition, dosage form, kit, or medicamentcomprises at least about 7.5% by weight water, relative to the totalweight of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt present inthe trihydrate form, and (if present) the anhydrous form. The watercontent of the bulk composition, pharmaceutical composition, dosageform, kit, or medicament includes the water present in the trihydrateform of the compound.

In some embodiments, the bulk composition, pharmaceutical composition,dosage form, kit, or medicament provided herein further comprises ananhydrous form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. Incertain embodiments, the ratio of Compound 1 to the anhydrous form is atleast about 2 to 1, at least about 3 to 1, at least about 4 to 1, atleast about 5 to 1, at least about 6 to 1, at least about 7 to 1, atleast about 8 to 1, at least about 9 to 1, at least about 10 to 1, atleast about 11 to 1, or at least about 12 to 1. In some embodiments, thebulk composition, pharmaceutical composition, dosage form, kit, ormedicament comprises an anhydrous form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, and theratio of Compound 1 to the anhydrous form is at least 4 to 1, or atleast 11 to 1.

E. Stability

In some embodiments, the bulk compositions, pharmaceutical compositions,dosage forms, medicaments, or kits comprising Compound 1 provided hereinhave increased stability relative to bulk compositions, pharmaceuticalcompositions, dosage forms, medicaments, or kits comprising theanhydrous form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt. Forexample, in some embodiments, the bulk compositions, pharmaceuticalcompositions, dosage forms, medicaments, or kits comprising Compound 1provided herein have a more stable weight over time compared to bulkcompositions, pharmaceutical compositions, dosage forms, medicaments, orkits comprising the anhydrous compound. In certain embodiments, the bulkcompositions, pharmaceutical compositions, dosage forms, medicaments, orkits comprising Compound 1 provided herein have less than 10%, less than9%, less than 8%, less than 7%, less than 6%, less than 5%, less than4%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, lessthan 1%, or less than 0.5% change in mass over at least 3 months, atleast 6 months, at least 9 months, at least 12 months, at least 15months, at least 18 months, at least 24 months, at least 30 months, atleast 36 months, at least 42 months, or at least 48 months. In someembodiments, the change in mass is an increase in mass. In someembodiments, the change in mass is a decrease in mass. In someembodiments, the bulk compositions, pharmaceutical compositions, dosageforms, medicaments, or kits comprising Compound 1 are more stable incertain conditions than bulk compositions, pharmaceutical compositions,dosage forms, medicaments, or kits comprising the anhydrous compound.For example, in some embodiments, the environment has a relativehumidity of greater than 10%, greater than 20%, greater than 30%,greater than 40%, greater than 50%, greater than 60%, greater than 70%,greater than 80%, greater than 90%, 10% or greater, 20% or greater, 30%or greater, 40% or greater, 50% or greater, 60% or greater, 70% orgreater, 80% or greater, or about 60%. In some embodiments, thetemperature is between 15° C. and 35° C. or between 20° C. and 30° C. Incertain embodiments, the temperature is about 25° C. In otherembodiments, the temperature is less than 35° C., less than 30° C.,greater than 10° C., greater than 15° C., or greater than 20° C. Incertain embodiments, the bulk compositions, pharmaceutical compositions,dosage forms, medicaments, or kits comprising Compound 1 provided hereinhave less than 8%, less than 4%, or less than 2% change in mass (such asincrease in mass) over at least 3 months, at least 6 months, at least 9months, at least 12 months, at least 18 months, at least 24 months, orat least 36 months when stored in an environment between 15° C. and 35°C. (such as between 20° C. and 30° C., or about 25° C.) and a relativehumidity of greater than 30% (such as greater than 50%, or about 60%).

II. METHODS OF USING COMPOUND 1

Further provided herein are methods of treating a disorder in a subjectin need thereof, comprising administering to the subject in need thereofa therapeutically effective amount of Compound 1. In some embodiments, apharmaceutical composition comprising Compound 1 and a pharmaceuticallyacceptable excipient is administered to the subject. Further providedherein are methods of improving gastrointestinal motility in a subjectin need thereof, comprising administering to the subject in need thereofa therapeutically effective amount of Compound 1, or administering apharmaceutical composition comprising Compound 1 and apharmaceutically-acceptable excipient. In addition, provided herein isthe use of Compound 1, or a pharmaceutical composition comprisingCompound 1, in treating a disorder in a subject in need thereof or forimproving gastrointestinal motility in a subject in need thereof, anduse of Compound 1 in the manufacture of a medicament for treating adisorder in a subject in need thereof or for improving gastrointestinalmotility in a subject in need thereof.

In some embodiments of treating a disorder in a subject in eed thereof(such as methods, use of Compound 1, use of a pharmaceutical compositioncomprising Compound 1, or use of Compound 1 in the manufacture of amedicament), the disorder is a gastrointestinal disorder. In someembodiments of improving gastrointestinal motility- in a subject in needthereof (such as methods, use of Compound 1, use a pharmaceuticalcomposition comprising Compound 1, or use of Compound 1 in themanufacture of a medicament), the subject in need thereof has agastrointestinal disorder. In certain embodiments, the gastrointestinaldisorder is gastroesophageal reflux disease (GERD), dyspepsia (such asfunctional dyspepsia or functional motility disorder), gastroparesis,paralytic ileus, post-operative ileus, emesis, nausea, heartburn,intestinal pseudo-obstruction, irritable bowel syndrome (IBS),constipation, enteral feeding intolerance (EFI), esophagitisis, chronicgrass sickness, megacolon, gastritis, gastrointestinal stasis, orabomasal emptying defect.

In some embodiments, the subject in need thereof is a human. In certainembodiments, wherein the subject in need thereof is a human, thegastrointestinal disorder is gastroesophageal reflux disease (GERD),dyspepsia (such as functional dyspepsia or functional motilitydisorder), gastroparesis, paralytic ileus, post-operative ileus, emesis,nausea, heartburn, intestinal pseudo-obstruction, irritable bowelsyndrome (IBS), constipation, enteral feeding intolerance (EFI), oresophagitisis. In other embodiments, the subject in need thereof is anon-human mammal, such as a ruminant (e.g., sheep, cow, yak, bison, orbuffalo), an equine (e.g., a horse (including a pony) or donkey), a cat,a dog, a rabbit, or a guinea pig. In some embodiments, wherein thesubject in need therein is a non-human mammal, the gastrointestinaldisorder is post-operative ileus, chronic grass sickness, constipation,megacolon, gastritis, gastrointestinal stasis, or abomasal emptyingdefect.

In some embodiments, provided herein is a method of treatinggastroesophageal reflux disease (GERD) in a subject in need thereof,comprising administering to the subject in need thereof atherapeutically effective amount of Compound 1, or administering to thesubject in need thereof a pharmaceutical composition comprising atherapeutically effective amount of Compound 1 and a pharmaceuticallyacceptable excipient. In some embodiments, provided herein is Compound1, or a pharmaceutical composition comprising Compound 1, for use intreating GERD, or use of Compound 1 in manufacturing a medicament fortreating GERD. In some embodiments of methods of treatment, Compound 1for use in, or a pharmaceutical composition comprising Compound 1 foruse in, or use of Compound in manufacturing a medicament for improvinggastrointestinal motility in a subject in need thereof, the subject inneed thereof has a gastrointestinal disorder, wherein thegastrointestinal disorder is GERD. GERD is a disease characterized asthe backward flow of the stomach contents into the esophagus. Oneimportant factor in the pathogenesis of gastroesophageal reflux diseaseis a reduction in the pressure barrier due to the failure of the loweresophageal sphincter. Failure of the lower esophageal sphincter canarise due to a low basal pressure, sphincter relaxation, or to anon-compensated increase in intragastric pressure. Other factors in thepathogenesis of the disease may include delayed gastric emptying,insufficient esophageal clearing due to impaired peristalsis, or thecorrosive nature of the reflux material, which can damage esophagealmucosa. In some embodiments, the GERD is proton pump inhibitor (PPI)resistant GERD. PPI resistant GERD may include, for example, GERD insubjects that which does not improve with administration of a PPI, or inwhich the main complaint of the subject has improved less than 50% withadministration of a PPI. Thus, in some embodiments, provided herein is amethod of treating; Compound 1 for use in treating; a pharmaceuticalcomposition comprising Compound 1 for use in treating; or use ofCompound 1 in manufacturing a medicament for treating GERD, wherein theGERD is PPI-resistant GERD. In some embodiments, the subject in needthereof is human.

In some embodiments, provided herein is a method of treating dyspepsiain a subject in need thereof, comprising administering to the subject inneed thereof a therapeutically effective amount of Compound 1, oradministering to the subject in need thereof a pharmaceuticalcomposition comprising a therapeutically effective amount of Compound 1and a pharmaceutically acceptable excipient. In some embodiments,provided herein is Compound 1, or a pharmaceutical compositioncomprising Compound 1, for use in treating dyspepsia, or use of Compound1 in manufacturing a medicament for treating dyspepsia. In someembodiments of methods of treatment, Compound 1 for use in, apharmaceutical composition comprising Compound 1 for use in, or use ofCompound in manufacturing a medicament for improving gastrointestinalmotility in a subject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder isdyspepsia. Dyspepsia is a condition characterized by an impairment ofthe power or function of digestion, and can arise as a symptom of aprimary gastrointestinal dysfunction or as a complication of otherdisorders, such as appendicitis, gallbladder disorders, or malnutrition.Thus, in some embodiments, treating dyspepsia comprises treatingdyspepsia associated with appendicitis, treating dyspepsia associatedwith a gallbladder disorder, or treating dyspepsia associated withmalnutrition, or treating functional dyspepsia (FD), or treating all ofthese. In some embodiments, treating dyspepsia is treating functionaldyspepsia (FD). Functional dyspepsia may also be called functionalmotility disorder (FMD). In some embodiments, the subject in needthereof is human. In other embodiments, the subject in need thereof is anon-human animal, such as a ruminant (such as a sheep, cow, yak, bison,or buffalo), or an equine (such as a horse (which may include a pony) ordonkey), a cat, a dog, a rabbit, or a guinea pig.

In some embodiments, provided herein is a method of treatinggastroparesis in a subject in need thereof, comprising administering tothe subject in need thereof a therapeutically effective amount ofCompound 1, or administering to the subject in need thereof apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating gastroparesis, oruse of Compound 1 in manufacturing a medicament for treatinggastroparesis. In some embodiments of methods of treatment, Compound 1for use in, a pharmaceutical composition comprising Compound 1 for usein, or use of Compound in manufacturing a medicament for improvinggastrointestinal motility in a subject in need thereof, the subject inneed thereof has a gastrointestinal disorder, wherein thegastrointestinal disorder is gastroparesis. Gastroparesis is a paralysisof the stomach brought about by a motor abnormality in the stomach, andcan be a complication of a disease such as diabetes, progressivesystemic sclerosis, anorexia nervosa, or myotonic dystrophy. In someembodiments, treating gastroparesis comprises treating diabeticgastroparesis, treating gastroparesis associated with progressivesystemic sclerosis, treating gastroparesis associated with anorexianervosa, or treating gastroparesis associated with myotonic dystrophy,or treating any combination of these. In some embodiments, thegastroparesis is idiopathic gastroparesis, or functional gastroparesis.In some embodiments, the subject in need thereof is human.

In some embodiments, provided herein is a method of treating paralyticileus in a subject in need thereof, comprising administering to thesubject in need thereof a therapeutically effective amount of Compound1, or administering to the subject in need thereof a pharmaceuticalcomposition comprising a therapeutically effective amount of Compound 1and a pharmaceutically acceptable excipient. In some embodiments,provided herein is Compound 1, or a pharmaceutical compositioncomprising Compound 1, for use in treating paralytic ileus, or use ofCompound 1 in manufacturing a medicament for treating paralytic ileus.In some embodiments of methods of treatment, Compound 1 for use in, apharmaceutical composition comprising Compound 1 for use in, or use ofCompound in manufacturing a medicament for improving gastrointestinalmotility in a subject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder isparalytic ileus. In some embodiments, the subject in need thereof ishuman.

In some embodiments, provided herein is a method of treatingpost-operative ileus in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of Compound 1, or administering to the subject in need thereof apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating post-operativeileus, or use of Compound 1 in manufacturing a medicament for treatingpost-operative ileus. In some embodiments of methods of treatment,Compound 1 for use in, a pharmaceutical composition comprising Compound1 for use in, or use of Compound in manufacturing a medicament forimproving gastrointestinal motility in a subject in need thereof, thesubject in need thereof has a gastrointestinal disorder, wherein thegastrointestinal disorder is post-operative ileus. Post-operative ileusis an obstruction in the intestine due to a disruption in muscle tonefollowing surgery. In some embodiments of treating post-operative ileus,the subject in need thereof is a human. In other embodiments, thesubject in need thereof is a non-human animal, such as an equine animal,for example a horse (which may include a pony).

In some embodiments, provided herein is a method of treating nausea oremesis in a subject in need thereof, comprising administering to thesubject in need thereof a therapeutically effective amount of Compound1, or administering to the subject in need thereof a pharmaceuticalcomposition comprising a therapeutically effective amount of Compound 1and a pharmaceutically acceptable excipient. In some embodiments,provided herein is Compound 1, or a pharmaceutical compositioncomprising Compound 1, for use in treating nausea, or use in treatingemesis, or use of Compound 1 in manufacturing a medicament for treatingnausea, or for treating emesis. In some embodiments of methods oftreatment, Compound 1 for use in, a pharmaceutical compositioncomprising Compound 1 for use in, or use of Compound in manufacturing amedicament for improving gastrointestinal motility in a subject in needthereof, the subject in need thereof has a gastrointestinal disorder,wherein the gastrointestinal disorder is nausea. In other embodiments,the gastrointestinal disorder is emesis. In some embodiments, thesubject in need thereof is human.

In some embodiments, provided herein is a rriethod of treating heartburnin a subject in need thereof, comprising administering to the subject inneed thereof a therapeutically effective amount of Compound 1, oradministering to the subject in need thereof a pharmaceuticalcomposition comprising a therapeutically effective amount of Compound 1and a pharmaceutically acceptable excipient. In some embodiments,provided herein is Compound 1, or a pharmaceutical compositioncomprising Compound 1, for use in treating heartburn, or use of Compound1 in manufacturing a medicament for treating heartburn. In someembodiments of methods of treatment, Compound 1 for use in, apharmaceutical composition comprising Compound 1 for use in, or use ofCompound in manufacturing a medicament for improving gastrointestinalmotility in a subject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder isheartburn. In some embodiments, the subject in need thereof is human.

In some embodiments, provided herein is a method of treating intestinalpseudo-obstruction in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of Compound 1, or administering to the subject in need thereof apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating intestinalpseudo-obstruction, or use of Compound 1 in manufacturing a medicamentfor treating intestinal pseudo-obstruction. In some embodiments ofmethods of treatment, Compound 1 for use in, a pharmaceuticalcomposition comprising Compound 1 for use in, or use of Compound inmanufacturing a medicament for improving gastrointestinal motility in asubject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder isintestinal pseudo-obstruction. Intestinal pseudo-obstruction is acondition characterized by constipation, colicky pain, and vomiting, butwithout evidence of physical obstruction. In some embodiments, treatingintestinal pseudo-obstruction comprises treating constipation associatedwith intestinal pseudo-obstruction, treating colicky pain associatedwith intestinal pseudo-obstruction, or treating vomiting associated withintestinal pseudo-obstruction, or treating all of these. In someembodiments, the subject in need thereof is human.

In some embodiments, provided herein is a method of treating irritablebowel syndrome (IBS) in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of Compound 1, or administering to the subject in need thereof apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating IBS, or use ofCompound 1 in manufacturing a medicament for treating IBS. In someembodiments of methods of treatment, Compound 1 for use in, apharmaceutical composition comprising Compound 1 for use in, or use ofCompound in manufacturing a medicament for improving gastrointestinalmotility in a subject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder is IBS.IBS is a condition that is characterized by abdominal pain due toabnormal colon contractions, and is often associated with constipationand diarrhea. Thus, in some embodiments, treating IBS comprises treatingabdominal pain associated with IBS, or treating constipation associatedwith IBS, or treating diarrhea with IBS. In some embodiments, the IBS isirritable bowel syndrome constipation type (IBSc). In some embodiments,the subject in need thereof is human.

In some embodiments, provided herein is a method of treatingconstipation in a subject in need thereof, comprising administering tothe subject in need thereof a therapeutically effective amount ofCompound 1, or administering to the subject in need thereof apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating constipation, oruse of Compound 1 in manufacturing a medicament for treatingconstipation. In some embodiments of methods of treatment, Compound 1,or a pharmaceutical composition comprising Compound 1, for use in, oruse of Compound in manufacturing a medicament for improvinggastrointestinal motility- in a subject in need thereof, the subject inneed thereof has a gastrointestinal disorder, wherein thegastrointestinal disorder is constipation. Constipation is a conditioncharacterized by infrequent or difficult evacuation of feces, and mayresult from a condition such as lack of intestinal muscle tone orintestinal spasticity. Thus, in some embodiments, treating constipationcomprises treating constipation associated with low intestinal muscletone, treating constipation associated with intestinal spasticity,treating constipation associated with IBS, treating constipationassociated with intestinal pseudo-obstruction, treating opiate-inducedconstipation (OIC), treating chronic idiopathic constipation (CIC), ortreating constipation associated with irritable bowel constipation type(IBSc). In some embodiments, the constipation is chronic constipation.In some embodiments, the subject in need thereof is a human. In otherembodiments, the subject in need thereof is a non-human mammal, such asa cat, or a dog.

In some embodiments, provided herein is a method of treating enteralfeeding intolerance (EFI) in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of Compound 1, or administering to the subject in need thereof apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating EFI, or use ofCompound 1 in manufacturing a medicament for treating EFI. In someembodiments of methods of treatment, Compound 1 for use in, apharmaceutical composition comprising Compound 1 for use in, or use ofCompound in manufacturing a medicament for improving gastrointestinalmotility in a subject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder is EFI.EFI in critical-illness patients is common. It is often characterized byone or more of vomiting, abdominal distention, complaints of discomfort,high nasogastric tube output, high gastric residual volumes (GRVs)measured at intervals, diarrhea, reduced passage of flatus and stool, orabnormal abdominal radiographs. Critical-illness patients suffering fromEFI are associated with a longer stay in ICU and reduced survival. Insome embodiments, treating EFI comprises one or more of treatingvomiting associated with EFI, treating abdominal distention associatedwith EFI, treating discomfort associated with EFI, treating highnasogastric tube output associated with EFI, treating high gastricresidual volumes (GRVs) associated with EFI, treating diarrheaassociated with EFI, or treating reduced passage of flatus and stoolassociated with EFI. In some embodiments, the subject in need thereof ishuman.

In still further embodiments, provided herein is a method of treatingesophagitis in a subject in need thereof, comprising administering tothe subject in need thereof a therapeutically effective amount ofCompound 1, or administering to the subject in need thereof apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating esophagitis, oruse of Compound 1 in manufacturing a medicament for treatingesophagitis. In some embodiments of methods of treatment, Compound 1 foruse in, a pharmaceutical composition comprising Compound 1 for use in,or use of Compound in manufacturing a medicament for improvinggastrointestinal motility in a subject in need thereof, the subject inneed thereof has a gastrointestinal disorder, wherein thegastrointestinal disorder is esophagitis. Esophagitis includesinflammation of the lining of the esophagus, and may be caused by, forexample backflow of acid from the stomach into the esophagus (forexample, in GERD), or allergic inflammation of the esophageal tissue. Insome embodiments, the esophagitis is erosive esophagitis (EE) oreosinophilic esophagitis (EoE). Thus, in some embodiments treatingesophagitis includes treating erosive esophagitis or eosinophilicesophagitis. In some embodiments, the subject in need thereof is human.

In further embodiments, provided herein is a method of treating chronicgrass sickness in a subject in need thereof, comprising administering tothe subject in need thereof a therapeutically effective amount ofCompound 1, or a pharmaceutical composition comprising a therapeuticallyeffective amount of Compound 1 and a pharmaceutically acceptableexcipient. In some embodiments, provided herein is Compound 1, or apharmaceutical composition comprising Compound 1, for use in treatingchronic grass sickness, or use of Compound 1 in manufacturing amedicament for treating chronic grass sickness in a subject in needthereof. In some embodiments of methods of treatment, Compound 1 for usein, a pharmaceutical composition comprising Compound 1 for use in, oruse of Compound in manufacturing a medicament for improvinggastrointestinal motility in a subject in need thereof, the subject inneed thereof has a gastrointestinal disorder, wherein thegastrointestinal disorder is chronic grass sickness. In some embodimentsof the methods of treatment, Compound 1 for use in, a pharmaceuticalcomposition comprising Compound 1 for use in, or use of Compound inmanufacturing a medicament for treating chronic grass sickness in asubject in need thereof, the subject in need thereof is a non-humananimal, such as an equine or a ruminant. In some embodiments, the equineis a horse (which may be a pony) or a donkey. In some embodiments, theruminant is a sheep. Chronic grass sickness includes impaired activityof the gut due to damage to the autonomic (involuntary) nervous system,and is a form of autonomic dystonia. Chronic grass sickness in an equinemay also be known as equine dysautonomia.

In other embodiments, provided herein is a method of treating megacolonin a subject in need thereof, comprising administering to the subject inneed thereof a therapeutically effective amount of Compound 1, or apharmaceutical composition comprising a therapeutically effective amountof Compound 1 and a pharmaceutically acceptable excipient. In someembodiments, provided herein is Compound 1, or a pharmaceuticalcomposition comprising Compound 1, for use in treating megacolon, or useof Compound 1 in manufacturing a medicament for treating megacolon. Insome embodiments of methods of treatment, Compound 1 for use in, apharmaceutical composition comprising Compound 1 for use in, or use ofCompound in manufacturing a medicament for improving gastrointestinalmotility in a subject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder ismegacolon. In some embodiments of methods of treatment. Compound 1 foruse in, a pharmaceutical composition comprising Compound 1 for use in,or use of Compound in manufacturing a medicament for treating megacolonin a subject in need thereof, the subject in need thereof is a non-humananimal, such as a companion animal. In certain embodiments, the subjectin need thereof is a cat or a dog. Megacolon includes an abnormaldilation of the colon (also called the large intestine), and is oftenaccompanied by a paralysis of the peristaltic movements of the bowel.

In still further embodiments, provided herein is a method of treatinggastritis in a subject in need thereof, comprising administering to thesubject in need thereof a therapeutically effective amount of Compound1, or a pharmaceutical composition comprising a therapeuticallyeffective amount of Compound 1 and a pharmaceutically acceptableexcipient. In some embodiments, provided herein is Compound 1, or apharmaceutical composition comprising Compound 1, for use in treatinggastritis, or use of Compound 1 in manufacturing a medicament fortreating gastritis. In some embodiments of methods of treatment,Compound 1 for use in, a pharmaceutical composition comprising Compound1 for use in, or use of Compound in manufacturing a medicament forimproving gastrointestinal motility in a subject in need thereof, thesubject in need thereof has a gastrointestinal disorder, wherein thegastrointestinal disorder is gastritis. In some embodiments of methodsof treatment, Compound 1 for use in, a pharmaceutical compositioncomprising Compound 1 for use in, or use of Compound in manufacturing amedicament for treating gastritis in a subject in need thereof, thesubject in need thereof is a non-human animal, such as a companionanimal. In certain embodiments, the subject in need thereof is a cat. Incertain embodiments, the gastritis is atrophic gastritis. Gastritis isan inflammation of the gastric mucosa, and symptoms may include acutevomiting, decreased appetite, dehydration, lethargy or depression,increased thirst, blood in the vomit or feces, and abdominal pain.

In certain embodiments, provided herein is a method of treatinggastrointestinal stasis in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of Compound 1, or a pharmaceutical composition comprising atherapeutically effective amount of Compound 1 and a pharmaceuticallyacceptable excipient. In some embodiments, provided herein is Compound1, or a pharmaceutical composition comprising Compound 1, for use intreating gastrointestinal stasis, or use of Compound 1 in manufacturinga medicament for treating gastrointestinal stasis in a subject in needthereof. In some embodiments of methods of treatment, Compound 1 for usein, a pharmaceutical composition comprising Compound 1 for use in, oruse of Compound in manufacturing a medicament for treatinggastrointestinal stasis, the subject in need thereof is a rabbit or aguinea pig. Gastrointestinal stasis is the slowdown or completecessation of gastrointestinal movement. In, for example, rabbits orguinea pigs, the intestine can become static for a variety of reasons,which may include stress, dehydration, pain from another underlyingdisorder or illness (such as gas, dental problems, infections, orurinary tract disorders), an intestinal blockage, or insufficientdietary crude fiber. Left untreated, the slowdown or complete cessationof normal intestinal movement (peristalsis) can result in death.

In other embodiments, provided herein is a method of treating abomasalemptying defect in a subject in need thereof, comprising administeringto the subject in need thereof a therapeutically effective amount ofCompound 1, or a pharmaceutical composition comprising a therapeuticallyeffective amount of Compound 1 and a pharmaceutically acceptableexcipient. In some embodiments, provided herein is Compound 1, or apharmaceutical composition comprising Compound 1, for use in treatingabomasal emptying defect, or use of Compound 1 in manufacturing amedicament for treating abomasal emptying defect. In some embodiments ofmethods of treatment, Compound 1 for use in, a pharmaceuticalcomposition comprising Compound 1 for use in, or use of Compound inmanufacturing a medicament for improving gastrointestinal motility in asubject in need thereof, the subject in need thereof has agastrointestinal disorder, wherein the gastrointestinal disorder isabomasal emptying defect. In some embodiments of methods of treatment,Compound 1 for use in, a pharmaceutical composition comprising Compound1 for use in, or use of Compound in manufacturing a medicament fortreating abomasal emptying defect in a subject in need thereof, thesubject in need thereof is a non-human animal, such as a ruminant, forexample a domesticated ruminant. In some embodiments, the ruminant is asheep, cow (which may include a bull), yak, bison, or buffalo. Abomasalemptying defect is the slowdown or complete cessation of abomasumemptying, characterized by distension and impaction of the abomasum.

In some embodiments, provided herein is a method of increasing thetransfer of passive immunity to a colostrum-fed calf, comprisingadministering to the calf an effective amount of Compound 1, or apharmaceutical composition comprising an effective amount of Compound 1and a pharmaceutically acceptable excipient. In some embodiments,provided herein is Compound 1, or a pharmaceutical compositioncomprising Compound 1, for use in increasing the transfer of passiveimmunity to a colostrum-fed calf, or use of Compound 1 in manufacturinga medicament for increasing the transfer of passive immunity to acolostrum-fed calf. In some embodiments, the colostrum-fed calf is acolostrum-fed dairy calf. Neonatal calves must ingest colostrum duringthe first 24 hours after birth to acquire passive immunity via theactive uptake of maternal IgG (maternal antibodies) across smallintestinal epithelial cells. The mass of IgG absorbed from the smallintestine of the colostrum-fed calf may depend, in part, on the rate ofabomasal emptying (rate of emptying of the abomasum, the fourth chamberof the ruminants' stomach). The rate of abomasal emptying may influencethe rate at which colostral IgG is delivered to the site of IgGabsorption in the small intestine. An increased rate of abomasalemptying may, in some embodiments, result in an increased apparentefficiency of absorption because colostral IgG may reach the site ofabsorption in the small intestine earlier and at a higher luminalconcentration.

As described herein, provided are methods of treatment, Compound 1 foruse in, or a pharmaceutical composition comprising Compound 1 for usein, or use of Compound in manufacturing a medicament for improvinggastrointestinal motility in a subject in need thereof. Poorgastrointestinal motility can include poor motility of the stomach.,poor motility of the small intestine, poor motility of the largeintestine, or poor motility of the pelvic floor, or combinationsthereof. In some embodiments, poor gastrointestinal motility includescomplete cessation of motility. Symptoms associated with poorgastrointestinal motility may include, for example, constipation,vomiting, bloating, diarrhea, or nausea. In some embodiments, poorgastrointestinal motility is associated with a gastrointestinaldisorder, such as one of the gastrointestinal disorders describedherein. In certain embodiments, improving gastrointestinal motility asdescribed herein comprises improving gastric motility, or improvingintestinal motility, or a combination thereof. In certain embodiments,improving intestinal motility comprises improving the motility of thesmall intestine, or improving the motility of the large intestine, or acombination thereof. In some embodiments, improving gastrointestinalmotility includes increasing gastrointestinal smooth muscle activityfrom the esophagus through the proximal small bowel. In certainembodiments, this accelerates esophageal and small intestinal transit,and may also facilitate gastric emptying and increase lower esophagealsphincter tone. In some embodiments, improving gastrointestinal motilitycomprises treating functional motility disorder. Thus, in someembodiments, provided herein are methods of treatment, Compound 1 foruse in, or a pharmaceutical composition comprising Compound 1 for usein, or use of Compound in manufacturing a medicament for treatingfunctional motility disorder (FMD). Functional motility disorder mayalso be called functional dyspepsia (FD). In some embodiments ofimproving gastrointestinal motility, the subject in need thereof is ahuman. In other embodiments, the subject in need thereof is a non-humananimal, such as a ruminant (such as a sheep, cow, yak, bison, orbuffalo), or an equine (such as a horse (which may include a pony) ordonkey), a cat, a dog, a rabbit, or a guinea pig.

In some embodiments of the methods and uses provided herein, the subjectis a newborn. In some embodiments, the newborn is a newborn human. Inother embodiments, the newborn is a bovine newborn, such as acolostrum-fed calf. In some embodiments, Compound 1 or a pharmaceuticalcomposition comprising Compound 1 and a pharmaceutically acceptableexcipient is administered to the subject parenterally (such asintravenously). In some embodiments, it is administered subcutaneously.In other embodiments, it is administered intramuscularly. In stillfurther embodiments, it is administered intraperitoneally. In someembodiments, it is administered rectally. In certain embodiments, it isadministered orally. In other embodiments, it is administered through agastric tube. For example, in some embodiments a solid form of Compound1 (such as a powder, or tablets), or a solid pharmaceutical compositionscomprising Compound 1 (such as a powder or tablet compositionscomprising Compound 1) is dissolved in suitable medium to form a liquid,and the liquid administered parenterally (such as intravenously), ororally, or by a gastric tube. In certain embodiments, a solid form ofCompound 1, or a solid pharmaceutical composition comprising Compound 1,is administered orally to a subject in need thereof (e.g., as a powder,one or more tablets, or one or more capsules). In some embodiments, theCompound 1 administered to a subject in need thereof as described herein(such as in a pharmaceutical composition), or used in the manufacture ofa medicament as described herein, has one or more of the propertiesdescribed herein, for example a crystalline form with one or more XRPDpeaks as described herein.

In certain embodiments of any of the methods and uses provided herein(including, for example, methods of treating, Compound 1 for use, apharmaceutical composition comprising Compound 1 for use, or uses ofCompound 1 in manufacturing a medicament) for treating disordersdescribed herein, or for improving gastrointestinal motility asdescribed herein, in a subject in need thereof, the subject in needthereof is an animal. In some embodiments, the animal is a mammal. Incertain embodiments, the animal is a human. In other embodiments, theanimal is a non-human animal. In certain embodiments, the animal is aruminant, such as a domesticated ruminant. In some embodiments, theruminant is a sheep, cow (which may include a bull), yak, bison, orbuffalo, in other embodiments, the mammal is an equine, such as adomesticated equine. In certain embodiments, the equine is a horse(including a pony) or a donkey. In other embodiments, the animal is acat, a dog, a rabbit, or a guinea pig. In certain embodiments, theanimal is a companion animal, for example a pet horse, a pet donkey, apet cat, a pet dog, a pet rabbit, or a pet guinea pig. In otherembodiments, the animal is an animal used for food production, such as asheep, cow, bison, buffalo, or yak. Thus, provided herein are methodsof, Compound 1 for use in, a pharmaceutical composition comprisingCompound 1 for use, or uses of Compound 1 in manufacturing a medicamentfor, treating the disorders described herein, or for improvinggastrointestinal motility as described herein, in a human. In anotheraspect, provided herein are methods of, Compound 1 for use in, apharmaceutical composition comprising Compound 1 for use, or uses ofCompound 1 in manufacturing a medicament for, treating the disordersdescribed herein, or for improving gastrointestinal motility asdescribed herein, in a non-human mammal.

As described herein, provided are bulk compositions, pharmaceuticalcompositions, kits, and dosage forms comprising Compound 1 that haveparticular stability, or organic solvent content, or water content, orratios of trihydrate to anhydrous form, or XRPD spectra, or variouscombinations of these. Any of these pharmaceutical compositions, dosageforms, or kits may, in some embodiments, be used in the methods and usesdescribed herein for treating a disorder, or promoting gastrointestinalmotility, in a subject in need thereof as provided herein. In someembodiments, any of these bulk compositions may be used in the methodsand uses described herein for treating a disorder, or promotinggastrointestinal motility, in a subject in need thereof as providedherein, or may be used in the manufacture of a pharmaceuticalformulation or dosage form or kit for use in the methods and usesdescribed herein for treating a disorder, or promoting gastrointestinalmotility, in a subject in need thereof as provided herein.

III. METHODS OF PRODUCING COMPOUND 1

In some aspects, provided herein are methods of producing Compound 1,and bulk compositions comprising Compound 1. In developing methods toproduce bulk compositions of Compound 1, it has been surprisingly foundthat merely drying a wet mixture of di-hydrochloride salt of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester is does not always reliablyproduce a composition comprising Compound 1 with low (non-water)residual solvent. Rather, a stepped procedure of different temperaturesand pressure ranges is, in some embodiments, a key aspect of theprocedure to produce compositions comprising Compound 1 on a largescale. Furthermore, it has been found that there are at least threecrystalline forms of the anhydrous di-hydrochloride salt of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester, and at least one crystallineform of Compound 1 (the trihydrate), and under certain conditions ofsolvent and temperature certain of these forms can interchange. Themethods of making Compound 1 described herein may reproducibly yieldCompound 1 with low (non-water) residual solvent and may be suitable forboth laboratory scale and commercial scale manufacturing. The methods ofmaking Compound 1 may also yield a crystalline form that has goodhandling properties, for example, low clumping and/or flows well.

In some embodiments, the method of making Compound 1 (such as methods ofmaking a bulk composition comprising Compound 1) comprises:

-   -   (a) combining the free base (3S, 4R,        3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic        acid 1-azabicyclo[2.2.2]oct-3′-yl ester with organic solvent to        form a mixture;    -   (b) adjusting the pH of the mixture to between 3.5 and 4.5 by        the addition of hydrochloric acid;    -   (c) stifling the mixture until a precipitate is formed;    -   (d) isolating the precipitate to form an isolated precipitate;        and    -   (e) drying the isolated precipitate under reduced pressure to        produce the trihydrate form of (3S, 4R, 3′        R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic        acid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt        (Compound 1).

Any suitable organic solvent may be combined with the free base to formthe mixture. In some embodiments, the organic solvent comprises one ormore compounds, such as one or more organic compounds, or at least oneorganic compound and one or more non-organic compounds. In certainembodiments, the organic solvent comprises one or more alcohols. In someembodiments, the organic solvent comprises one or more C₁-C₈, or C₁-C₆,or C₁-C₄ alcohols. In certain embodiments, the organic solvent comprisesone or more of methanol, ethanol, n-propanol, or isopropanol. In someembodiments, the organic solvent comprises isopropanol. In someembodiments, the organic solvent comprises ethanol and n-propanol. Instill further embodiments, the organic solvent comprises at least oneorganic compound and one or more non-organic compounds.

In certain embodiments, the free base is combined with organic solventand water to form the mixture. For example, in some embodiments, thefree base is combined with water and organic solvent to form themixture, wherein the organic solvent comprises one or more alcohols,such as isopropanol. In some embodiments, the mixture may comprise, forexample, various amounts of water. In certain embodiments, the mixturecomprises organic solvent and at least 1% by weight water, at least 5%by weight water, at least 10% by weight water, no more than 20% byweight water, no more than 15% by weight water, no more than 10% byweight water, about 1% by weight to about 20% by weight water, about 5%by weight to about 15% by weight water, about 8% by weight to about 12%by weight water, or about 10% by weight water, wherein the weight % ofwater is relative to the weight of organic solvent in the mixture. Incertain embodiments, the mixture comprises organic solvent and about 5%by weight to about 15% by weight water, relative to the amount oforganic solvent. In other embodiments, the organic solvent comprisesabout 8% by weight to about 12% by weight water. In some embodiments,the mixture comprises organic solvent and about 10% by weight water. Incertain embodiments, the mixture comprises organic solvent, wherein theorganic solvent comprises one or more alcohols; and water, wherein thewater is present in about 5% by weight to about 15% by weight, about 8%by weight to about 12% by weight, or about 10% by weight, wherein theweight % of water is relative to the amount of organic solvent. In stillfurther embodiments, the mixture comprises organic solvent, wherein theorganic solvent comprises ethanol, n-propanol, or isopropanol, or anycombinations thereof; and water, wherein the water is present in about5% by weight to about 15% by weight, about 8% by weight to about 12% byweight, or about 10% by weight relative to the amount of organicsolvent. In still further embodiments, the mixture comprises organicsolvent, wherein the organic solvent comprises isopropanol; and water,wherein the water is present in about 5% by weight to about 15% byweight, about 8% by weight to about 12% by weight, or about 10% byweight relative to the amount of organic solvent. In certainembodiments, the mixture comprises water and organic solvent at a volumeratio of less than 3:7. In certain embodiments, the mixture compriseswater and organic solvent at a volume ratio of less than 1:4. In certainembodiments, the mixture comprises water and organic solvent ata volumeratio of less than 1:3, less than 1:4, less than 1:5, less than 1:6,less than 1:7, less than 1:8, or less than 1:9 by volume. In certainembodiments, the ratio is about 1:9. In any of these embodiments, theorganic solvent may comprise one or more C₁-C₈, or C₁-C₆, or C₁-C₄alcohols. In some embodiments, the organic solvent comprises ethanol andn-propanol. In certain embodiments, the organic solvent comprisesisopropanol. In certain embodiments, the organic solvent is isopropanol.In some embodiments, a mixture comprising water and organic solvent at avolume ratio of less than 3:7 by volume (such as less than 1:4, forexample about 1:9) results in a higher yield of a crystalline form ofCompound 1 than a process using a mixture with a higher ratio of waterand organic solvent.

In certain embodiments, the pH of the mixture is adjusted withhydrochloric acid by adding aqueous solution of hydrochloric acid to themixture formed by the free base and the organic solvent, and optionallywater. For example, in some embodiments, the hydrochloric acid isconcentrated hydrochloride acid. In certain embodiments, thehydrochloride acid is added as an aqueous solution comprising from about30% to about 45% by weight hydrochloric acid, or about 30% to about 40%by weight hydrochloric acid, or about 35% to about 40% by weighthydrochloric acid, or about 37% by weight hydrochloric acid. In someembodiments, aqueous hydrochloric acid of a different strength is used,for example 20% by weight, or 15% by weight, or 10% by weight, or 5% byweight aqueous hydrochloric acid. In other embodiments, the pH of themixture is adjusted with hydrochloric acid by bubbling gaseous hydrogenchloride through the mixture to form hydrochloric acid. In someembodiments of the methods provided herein, the pH of the mixture isadjusted to between 3.5 to 4.5, or to between 3.6 to 4.4, or to between3.7 to 4.3, or to between 3.8 to 4.2, or to between 3.9 to 4.1, or toabout 4.0 by the addition of hydrochloric acid.

In some embodiments, the mixture is stirred at a temperature of lessthan 50° C. until a precipitate is formed. In some embodiments, themixture is stirred at a temperature of 45° C. or less, 40° C. or less,35° C. or less, 30° C. or less, 25° C. or less, or 20° C. or less tountil a precipitate is formed. In certain embodiments, the mixture isstirred at a temperature between 20° C. to 45° C., between 20° C. to 40°C., between 20° C. to 35° C., between 25° C. to 45° C., between 25° C.to 40° C., or between 25° C. to 35° C. until a precipitate is formed. Insome embodiments, the mixture is stirred at a temperature of 30° C. orless until a precipitate is formed. In certain embodiments, stirring themixture at a temperature of less than 50° C. (such as, for example,between 20° C. to 40° C., or between 25° C. to 35° C., or about 30° C.)until a precipitate is formed results in a higher yield of a crystallineform of Compound 1 from the process than stirring the mixture at ahigher temperature.

In certain embodiments, after the precipitate is formed, it is isolatedto produce the isolated precipitate. In certain embodiments, theprecipitate is isolated directly from the mixture to form the isolatedprecipitate. In other embodiments, one or more steps occur after formingthe precipitate prior to isolating the precipitate to form the isolatedprecipitate, such as one or more recrystallization steps. Theprecipitate may be isolated by any suitable means, such ascentrifugation, filtration, or other means, to form an isolatedprecipitate. The isolated precipitate may undergo one or more additionalsteps (such as one or more wash steps) prior to being dried underreduced pressure.

In certain embodiments, which may be combined with any other embodimentsdescribed herein, water is added at one or more steps prior to dryingthe isolated precipitate under reduced pressure. For example, in someembodiments, the free base is combined with organic solvent and water toform a mixture; or water is added to the mixture formed by combining thefree base and the organic solvent; or water is added with hydrochloricacid to adjust the pH of the mixture; or water is added to the mixtureafter the pH has been adjusted; or water is added to the mixture afterthe precipitate is formed but prior to isolating the precipitate; orwater is added during or before or after any of the additional stepsdescribed herein, such as recrystallization or washing. In someembodiments, water is added two or more times during the method, such asbeing combined with the organic solvent and the free base to form amixture, and while adjusting the pH of the mixture by addition ofhydrochloric acid.

A. Water and Organic Solvent Content

In some embodiments, the isolated precipitate is dried under reducedpressure until a water content of between 6.5% by weight to 10% byweight is reached to produce Compound 1. In certain embodiments, theisolated precipitate is dried under reduced pressure, such as reducedpressures described here, until a water content of between 6.5% byweight, 6.6% by weight 6.7% by weight, 6.8% weight, 6.9% by weight, 7.0%by weight, 7.1% by weight, 7.2% by weight, 7.3% by weight, 7.4% byweight, 7.5% by weight, 7.6% by weight, 7.7% by weight, 7.8% by weight,7.9% by weight, or 8.0% by weight to 8.4% by weight, 8.5% by weight,8.6% by weight 8.7% by weight, 8.8% weight, 8.9% by weight, 9.0% byweight, 9.1% by weight, 9.2% by weight, 9.3% by weight, 9.4% by weight,9.5% by weight, 9.6% by weight 9.7% by weight, 9.8% weight, 9.9% byweight, or 10.0% by weight is reached. In some embodiments, the isolatedprecipitate is dried under reduced pressure until a water content ofbetween 7.5% by weight to 9.0% by weight is reached to produceCompound 1. In certain embodiments, the isolated precipitate is driedunder reduced pressure until a water content of between 7.6% by weightto 8.8% by weight is reached to produce Compound 1. In still furtherembodiments, the isolated precipitate is dried under reduced pressureuntil a water content of about 8.2% by weight is reached to produceCompound 1. The water content of the isolated precipitate includes thewater present in the trihydrate form (Compound 1).

In some embodiments, the isolated precipitate is dried under reducedpressure, such as reduced pressures described here, until the organicsolvent content is less than about 6000 ppm. In some embodiments, it isdried under reduced pressure until the organic solvent content is lessthan about 5500 ppm, less than about 5000 ppm, less than about 4500 ppm,less than about 4000 ppm, less than about 3500 ppm, less than about 3000ppm, less than about 2500 ppm, or less than about 2000 ppm. In certainembodiments, it is dried under reduced pressure until the organicsolvent content is less than about 5000 ppm, or less than about 4000ppm. In some embodiments, the organic solvent comprises one or morealcohols. In some embodiments, the organic solvent comprises one or moreC₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. In certain embodiments, the organicsolvent comprises isopropanol, n-propanol, ethanol, or methanol, or anycombinations thereof. In some embodiments, the organic solvent compriseethanol and n-propanol. In some embodiments, the organic solventcomprises isopropanol.

B. Drying Conditions

In some embodiments, the reduced pressure used to dry the isolatedprecipitate is between about 20 mm Hg to about 60 mm Hg, or betweenabout 20 mm Hg to about 55 mm Hg, or between about 20 mm Hg to about 50mm Hg, or between about 25 mm Hg to about 50 mm Hg, or about 25 mm Hg toabout 45 mm Hg, or about 30 mm Hg to about 40 mm Hg, or about 35 mm Hg.In some embodiments, the reduced pressure is between about 20 mm Hg toabout 60 mm Hg. In other embodiments, the reduced pressure is from about25 mm Hg to about 50 mm Hg. In certain embodiments, the reduced pressureis from about 30 mm Hg to about 50 mm Hg. In still further embodiments,the reduced pressure is from about 30 mm Hg to about 40 mm Hg, or about35 mm Hg.

In some embodiments of the methods provided herein, the isolatedprecipitate is dried under reduced pressure at a temperature betweenabout 10° C. to about 70° C., or between about 20° C. to about 60° C.,or between about 25° C. to about 55° C., or between about 30° C. toabout 50° C. In some embodiments, the isolated precipitate is driedunder reduced pressure in one or more steps, for example, wherein thetemperature of the isolated precipitate is changed over time during thedrying process. In certain embodiments, drying the isolated precipitatestep-wise over a range of temperatures results in a composition (such asa bulk composition) comprising Compound 1 with a lower residual organicsolvent level than is achieved drying the isolated precipitate at singletemperature or narrower range of temperatures. For example, in someembodiments, drying the isolated precipitate step-wise produces acomposition (such as a bulk composition) comprising Compound 1 with aresidual organic solvent content of less than 6000 ppm. In otherembodiments, drying the isolated precipitate step-wise produces acomposition (such as a bulk composition) comprising Compound 1 with aresidual organic solvent content of less than about 5000 ppm, or lessthan about 4000 ppm, or less than about 3000 ppm, or less than about2000 ppm. In some embodiments, the organic solvent comprises one or morealcohols. In some embodiments, the organic solvent comprises one or moreC₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. In certain embodiments, the organicsolvent comprises isopropanol, n-propanol, ethanol, or methanol, or anycombinations thereof. In some embodiments, the organic solvent comprisesethanol and n-propanol. In still further embodiments, the organicsolvent comprises isopropanol.

In some embodiments, the isolated precipitate is dried under reducedpressure at a temperature between about 10° C. to about 50° C., and thenat a temperature between about 35° C. to about 70° C. to produceCompound 1. In certain embodiments, the isolated precipitate is driedunder reduced pressure at a temperature between about 20° C. to about50° C., and then at a temperature between about 35° C. to about 60° C.;or between about 25° C. to about 45° C., and then at a temperaturebetween about 40° C. to about 55° C. In certain embodiments, theisolated precipitate is dried under reduced pressure at a temperaturebetween about 20° C. to about 40° C.; then at a temperature betweenabout 30° C. to about 50° C.; then at a temperature between about 35° C.to about 55° C.; and then at a temperature between about 40° C. to about60° C. In certain embodiments, the isolated precipitate is dried underreduced pressure at a temperature between about 25° C. to about 35° C.,then at a temperature between about 35° C. to about 45° C., then at atemperature between about 40° C. to about 50° C., and then at atemperature between about 45° C. to about 55° C.

In some embodiments, the isolated precipitate is dried under reducedpressure for a specified period of time, and a specified temperature orrange of temperatures. For example, in certain embodiments, performing astep-wise drying comprises drying the isolated precipitate at thespecified temperature or temperature range for a particular period oftime. In certain embodiments, drying the isolated precipitate in such away provides a composition comprising Compound 1 (such as a bulkcomposition) with a lower level of residual organic solvent than wouldotherwise be achieved. In some embodiments, the isolated precipitate isdried under reduced pressure at a temperature between about 10° C. toabout 50° C. for about 0.5 hours to about 10 hours, and then at atemperature between about 35° C. to about 70° C. for about 0.5 hours toabout 10 hours to produce Compound 1 or a bulk composition comprisingCompound 1. In certain embodiments, the isolated precipitate is driedunder reduced pressure at a temperature between about 20° C. to about50° C. for about 0.5 hours to about 10 hours, and then at a temperaturebetween about 35° C. to about 60° C. for about 0.5 hours to about 10hours; or between about 25° C. to about 45° C. for about 0.5 hours toabout 10 hours, and then at a temperature between about 40° C. to about55° C. for about 0.5 hours to about 10 hours. In certain embodiments,the isolated precipitate is dried under reduced pressure at atemperature between about 20° C. to about 40° C. for about 0.5 hours toabout 4 hours; then at a temperature between about 30° C. to about 50°C. for about 0.5 hours to about 4 hours; then at a temperature betweenabout 35° C. to about 55° C. for about 0.5 hours to about 4 hours; andthen at a temperature between about 40° C. to about 60° C. In certainembodiments, the step of drying the isolated precipitate at atemperature of about 40° C. to about 60° C. is undertaken for about 0.5to 10 hours, or for about 2 to 10 hours, or for about 3 to 7 hours. Incertain embodiments, the isolated precipitate is dried under reducedpressure at a temperature between about 25° C. to about 35° C. for about0.5 hours to about 3 hours; then at a temperature between about 35° C.to about 45° C. for about 0.5 hours to about 3 hours; then at atemperature between about 40° C. to about 50° C. for about 0.5 hours toabout 3 hours; and then at a temperature between about 45° C. to about55° C. In still other embodiments, the isolated precipitate is driedunder reduced pressure at a temperature between about 25° C. to about35° C. for about 0.5 to about 2.5 hours; then at a temperature betweenabout 35° C. to about 45° C. for about 0.5 to about 2.5 hours; then at atemperature between about 40° C. to about 50° C. for about 0.5 to about2.5 hours; and then at a temperature between about 45° C. to about 55°C. In certain embodiments, the step of drying the isolated precipitateat a temperature of about 45° C. to about 55° C. is undertaken for about0.5 to 15 hours, or for about 2 to 12 hours, or for about 3 to 10 hours,or for about 3 to 7 hours, or for about 4 to 8 hours. In still otherembodiments, the isolated precipitate is dried under reduced pressure ata temperature about 30° C. for about 0.5 to about 2.5 hours; then at atemperature about 40° C. for about 0.5 to about 2.5 hours; then at atemperature of about 45° C. for about 0.5 to about 2.5 hours; and thenat a temperature of about 50° C. In certain embodiments, the step ofdrying the isolated precipitate at a temperature of about 50° C. isundertaken for about 0.5 to 15 hours, or for about 2 to 12 hours, or forabout 3 to 10 hours, or for about 3 to 7 hours, or for about 4 to 8hours.

In other embodiments of the methods provided herein, the isolatedprecipitate is dried under reduced pressure for between about 2 hours toabout 20 hours, between about 2 hours to about 18 hours, between about 2hours to about 16 hours, between about 2 hours to about 14 hours,between about 2 hours to about 12 hours, between about 2 hours to about10 hours, between about 2 hours to about 8 hours, between about 2 hoursto about 6 hours, about 3 hours to about 20 hours, between about 3 hoursto about 18 hours, between about 3 hours to about 16 hours, betweenabout 3 hours to about 14 hours, between about 3 hours to about 12hours, between about 3 hours to about 10 hours, between about 3 hours toabout 8 hours, between about 3 hours to about 6 hours, about 5 hours toabout 20 hours, between about 5 hours to about 18 hours, between about 5hours to about 16 hours, between about 5 hours to about 14 hours,between about 5 hours to about 12 hours, between about 5 hours to about10 hours, between about 5 hours to about 8 hours, between about 7 hoursto about 20 hours, between about 7 hours to about 18 hours, betweenabout 7 hours to about 16 hours, between about 7 hours to about 14hours, between about 7 hours to about 12 hours, or between about 7 hoursto about 10 hours. In other embodiments of the methods provided herein,the isolated precipitate is dried under reduced pressure for betweenabout 3 hours to about 10 hours. In other embodiments, the isolatedprecipitate is dried under reduced pressure for between about 5 hours toabout 10 hours. In still further embodiments, the isolated precipitateis dried under reduced pressure for between about 7 hours to about 10hours.

In some embodiments, between about 150 kg to about 400 kg or betweenabout 200 kg to about 300 kg of isolated precipitate is dried underreduced pressure for between about 3 hours to about 10 hours, or betweenabout 5 hours to about 10 hours, or between about 7 hours to about 10hours to produce Compound 1. In certain embodiments, the isolatedprecipitate (such as between about 150 kg to about 400 kg) is driedunder reduced pressure (for example between about 3 hours to about 12hours, or between about 5 hours to about 12 hours, or between about 3hours to about 10 hours, or between about 5 hours to about 10 hours, orbetween about 7 hours to about 10 hours) until there is less than about6000 ppm organic solvent, or less than about 5000 ppm organic solvent,or less than about 4000 ppm organic solvent, or less than about 3000 ppmorganic solvent, or less than about 2000 ppm organic solvent is reached,to produce Compound 1. In some embodiments, the organic solventcomprises one or more alcohols. In some embodiments, the organic solventcomprises one or more C₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. In certainembodiments, the organic solvent comprises isopropanol, n-propanol,ethanol, or methanol, or any combinations thereof. In some embodiments,the organic solvent comprises ethanol and n-propanol. In still furtherembodiments, the organic solvent comprises isopropanol.

In some embodiments, between about 150 kg to about 400 kg or betweenabout 200 kg to about 300 kg of isolated precipitate is dried underreduced pressure of from about 20 mm Hg to about 60 mm Hg, or from about25 mm Hg to about 45 mm Hg, or about 35 mm Hg, for between about 3 hoursto about 15 hours, or between about 5 hours to about 12 hours, orbetween about 7 hours to about 10 hours to produce Compound 1. Incertain embodiments, the isolated precipitate (such as between about 150kg to about 400 kg) is dried under reduced pressure (for example fromabout 20 mm Hg to about 60 mm Hg, or from about 25 mm Hg to about 45 mmHg, or about 35 mm Hg, for example between about 3 hours to about 15hours, or between about 5 hours to about 12 hours, or between about 7hours to about 10 hours) until there is less than about 6000 ppm organicsolvent, or less than about 5000 ppm organic solvent, or less than about4000 ppm organic solvent, or less than about 3000 ppm organic solvent,or less than about 2000 ppm organic solvent is reached, to produceCompound 1. In some embodiments, the organic solvent comprises one ormore alcohols. In some embodiments, the organic solvent comprises one ormore C₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. In certain embodiments, theorganic solvent comprises isopropanol, n-propanol, ethanol, or methanol,or any combinations thereof. In some embodiments, the organic solventcomprises ethanol and n-propanol. In still further embodiments, theorganic solvent comprises isopropanol.

For any of the methods of drying the isolated precipitate providedherein, in some embodiments the temperature recited is the temperatureof the isolated precipitate during drying. In other embodiments, it isthe temperature of one or more heating elements that is contacting atleast part of the isolated precipitate. For example, in some embodimentsthe temperature of the isolated precipitate is controlled during dryingusing a jacketed vessel. In some embodiments, the jacketed vessel is ajacketed batch reactor. In certain embodiments, the jacketed vessel is ajacketed vacuum dryer, such as a cone dryer, spiral dryer, or paddledryer. Thus, in some embodiments, the temperature recited in the methodsof drying the isolated precipitate is the temperature of the jacket ofthe jacketed vessel. In some embodiments, the isolated precipitate isdried using a cone dryer with a jacket, and the temperature recited inthe method is the temperature of the jacket.

In some embodiments, the use of one of the specified temperatures orpressures or times, or ranges of temperature or pressures or times, orany combinations thereof, results in a bulk composition comprisingCompound 1 that has a particular stability, or organic solvent content,or water content, or ratio of trihydrate to anhydrous form, or XRPDspectra, or various combinations of these, as described herein. In someembodiments, the temperatures or pressures or times, or ranges thereof,or combinations of any of the forgoing, as described herein for dryingthe isolated precipitate may be combined with, for example, any of thequantities of precipitate or isolated precipitate or free base orCompound 1 used in the described process; or one or more additionalsteps, such as recrystallization or washing; or any of the otherconditions or steps described herein.

C. Quantities

In some embodiments, the amount of time required to dry the isolatedprecipitate to produce Compound 1 is related to the amount of Compound 1being made, or the amount of the free base used, or the amount ofprecipitate that is isolated, or the amount of isolated precipitate thatis dried. In some embodiments, at least about 100 kg of the free base(3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester is combined with the organicsolvent, at least about 150 kg of the free base is combined with theorganic solvent, at least about 175 kg of the free base is combined withthe organic solvent, at least about 200 kg of the free base is combinedwith the organic solvent, at least about 250 kg of the free base iscombined with the organic solvent, at least about 300 kg of the freebase is combined with the organic solvent, at least about 350 kg of thefree base is combined with the organic solvent, at least about 400 kg ofthe free base is combined with the organic solvent, at least about 450kg of the free base is combined with the organic solvent, or at leastabout 500 kg of the free base is combined with the organic solvent. Insome embodiments, for example using a large-capacity reactor, at leastabout 1 metric ton of the free base is combined with the organicsolvent. In some embodiments, between about 100 kg to about 2,000 kg ofthe free base is combined with the organic solvent, between about 100 kgto about 1,000 kg of the free base is combined with the organic solvent,between about 100 kg to about 800 kg of the free base is combined withthe organic solvent, between about 100 kg to about 600 kg of the freebase is combined with the organic solvent, between about 100 kg to about400 kg of the free base is combined with the organic solvent, betweenabout 150 kg to about 2,000 kg of the free base is combined with theorganic solvent, between about 150 kg to about 1,000 kg of the free baseis combined with the organic solvent, between about 150 kg to about 800kg of the free base is combined with the organic solvent, between about150 kg to about 600 kg of the free base is combined with the organicsolvent, between about 150 kg to about 400 kg of the free base iscombined with the organic solvent, between about 150 kg to about 300 kgof the free base is combined with the organic solvent, between about 150kg to about 250 kg of the free base is combined with the organicsolvent, between about 200 kg to about 350 kg of the free base iscombined with the organic solvent, or between about 200 kg to about 300kg of the free base is combined with the organic solvent. As describedherein, in some embodiments the free base is combined with organicsolvent and water to make the mixture. Thus, for any of the amounts offree base that are combined with organic solvent as described herein, insome embodiments that amount of free base is combined with organicsolvent and water to form the mixture.

In some embodiments, at least about 100 kg of precipitate is isolated,at least about 150 kg of precipitate is isolated, at least about 175 kgof precipitate is isolated, at least about 200 kg of precipitate isisolated, at least about 250 kg of precipitate is isolated, at leastabout 300 kg of precipitate is isolated, at least about 350 kg ofprecipitate is isolated, at least about 400 kg of precipitate isisolated, at least about 450 kg of precipitate is isolated, or at leastabout 500 kg of precipitate is isolated. In certain embodiments, forexample using a large-capacity reactor, at least 1 metric ton ofprecipitate is isolated. In some embodiments, between about 100 kg toabout 2,000 kg of precipitate is isolated, between about 100 kg to about1,000 kg of precipitate is isolated, between about 100 kg to about 800kg of precipitate is isolated, between about 100 kg to about 600 kg ofprecipitate is isolated, between about 100 kg to about 400 kg ofprecipitate is isolated, between about 150 kg to about 2,000 kg ofprecipitate is isolated, between about 150 kg to about 1,000 kg ofprecipitate is isolated, between about 150 kg to about 800 kg ofprecipitate is isolated, between about 150 kg to about 600 kg ofprecipitate is isolated, between about 150 kg to about 400 kg ofprecipitate is isolated, between about 150 kg to about 300 kg ofprecipitate is isolated, between about 150 kg to about 250 kg ofprecipitate is isolated, between about 200 kg to about 350 kg ofprecipitate is isolated, or between about 200 kg to about 300 kg ofprecipitate is isolated.

In some embodiments, at least about 100 kg of isolated precipitate isdried, at least about 150 kg of isolated precipitate is dried, at leastabout 175 kg of isolated precipitate is dried, at least about 200 kg ofisolated precipitate is dried, at least about 250 kg of isolatedprecipitate is dried, at least about 300 kg of isolated precipitate isdried, at least about 350 kg of isolated precipitate is dried, at leastabout 400 kg of isolated precipitate is dried, at least about 450 kg ofisolated precipitate is dried, or at least about 500 kg of isolatedprecipitate is dried. In commercial, for example using a large-capacitydryer, at least 1 metric ton of isolated precipitate is dried. In someembodiments, between about 100 kg to about 2,000 kg of isolatedprecipitate is dried, between about 100 kg to about 1,000 kg of isolatedprecipitate is dried, between about 100 kg to about 800 kg of isolatedprecipitate is dried, between about 100 kg to about 600 kg of isolatedprecipitate is dried, between about 100 kg to about 400 kg of isolatedprecipitate is dried, between about 150 kg to about 2,000 kg of isolatedprecipitate is dried, between about 150 kg to about 1,000 kg of isolatedprecipitate is dried, between about 150 kg to about 800 kg of isolatedprecipitate is dried, between about 150 kg to about 600 kg of isolatedprecipitate is dried, between about 150 kg to about 400 kg of isolatedprecipitate is dried, between about 150 kg to about 300 kg of isolatedprecipitate is dried, between about 150 kg to about 250 kg of isolatedprecipitate is dried, between about 200 kg to about 350 kg of isolatedprecipitate is dried, or between about 200 kg to about 300 kg ofisolated precipitate is dried.

In still other embodiments, at least about 100 kg of Compound 1 isproduced, at least about 150 kg of Compound 1 is produced, at leastabout 175 kg of Compound 1 is produced, at least about 200 kg ofCompound 1 is produced, at least about 250 kg of Compound 1 is produced,at least about 300 kg of Compound 1 is produced, at least about 350 kgof Compound 1 is produced, at least about 400 kg of Compound 1 isproduced, at least about 450 kg of Compound 1 is produced, or at leastabout 500 kg of Compound 1 is produced. In certain embodiments, forexample using a commercial production facility, at least 1 metric ton ofCompound 1 is produced. In some embodiments, between about 100 kg toabout 2,000 kg of Compound 1 is produced, between about 100 kg to about1,000 kg of Compound 1 is produced, between about 100 kg to about 800 kgof Compound 1 is produced, between about 100 kg to about 600 kg ofCompound 1 is produced, between about 100 kg to about 400 kg of Compound1 is produced, between about 150 kg to about 2,000 kg of Compound 1 isproduced, between about 150 kg to about 1,000 kg of Compound 1 isproduced, between about 150 kg to about 800 kg of Compound 1 isproduced, between about 150 kg to about 600 kg of Compound 1 isproduced, between about 150 kg to about 400 kg of Compound 1 isproduced, between about 150 kg to about 300 kg of Compound 1 isproduced, between about 150 kg to about 250 kg of Compound 1 isproduced, between about 200 kg to about 350 kg of Compound 1 isproduced, or between about 200 kg to about 300 kg of Compound 1 isproduced.

D. Additional Steps

The methods of producing a bulk composition comprising Compound 1provided herein may, in some embodiments, comprise one or moreadditional steps.

For example, in some embodiments, after or during stifling the mixtureuntil a precipitate is formed in step (c), additional solvent is addedto the mixture before the precipitate is isolated. In some embodiments,the additional solvent comprises organic solvent. In certainembodiments, the organic solvent comprises one or more alcohols. In someembodiments, the organic solvent comprises one or more C₁-C₈, or C₁-C₆,or C₁-C₄ alcohols. In certain embodiments, the organic solvent comprisesisopropanol, n-propanol, ethanol, or methanol, or any combinationsthereof. In some embodiments, the organic solvent comprises ethanol andn-propanol. In still further embodiments, the organic solvent comprisesisopropanol. In some embodiments, the mixture in step (c) is adjustedsuch that it comprises water and organic solvent, wherein the water ispresent at between 5% to 15% by weight, or about 8% to about 12% byweight. In some embodiments, the mixture in step (c) is adjusted suchthat it comprises water and organic solvent at a volume ratio of lessthan 3:7. In some embodiments, the mixture in step (c) is adjusted suchthat it comprises water and organic solvent at a volume ratio of lessthan 1:4. In certain embodiments, the mixture in step (c) is adjustedsuch that it comprises water and organic solvent at a volume ratio ofless than 1:3, less than 1:4, less than 1:5, less than 1:6, less than1:7, less than 1:8, or less than 1:9 by volume. In certain embodiments,the ratio is about 1:9. In some embodiments, the organic solventcomprises one or more alcohols. In any of these embodiments, the organicsolvent may comprise one or more C₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. Insome embodiments, the organic solvent comprises ethanol and n-propanol.In certain embodiments, the organic solvent comprises isopropanol. Incertain embodiments, the organic solvent is isopropanol.

a. Recrystallization

In some embodiments, which may be combined with any of the otherembodiments described herein, the method of producing Compound 1comprises one or more recrystallization steps. Thus, for example, insome embodiments, after the isolated precipitate is formed in step (d),and before the isolated precipitate is dried in step (e), at least aportion of the isolated precipitate is dissolved in a recrystallizationsolvent to form a recrystallization mixture, the recrystallizationmixture is stirred until a recrystallized precipitate is formed, and therecrystallized precipitate is isolated to form an isolated precipitate.This isolated precipitate may, for example, be taken on to step (e) anddried to form Compound 1, or may, in some embodiments, be subject to oneor more additional steps, such as another recrystallization, or awashing step, or a combination thereof.

Any suitable recrystallization conditions may be used. In certainembodiments, a recrystallization solvent comprising water and organicsolvent is used. In some embodiments, the organic solvent comprises oneor more alcohols, for example isopropanol, n-propanol, ethanol, ormethanol, or any combinations thereof. In some embodiments, therecrystallization solvent comprises water and organic solvent, whereinthe water is present at between 5% to 15% by weight, or about 8% toabout 12% by weight. In some embodiments, the recrystallization solventcomprises water and organic solvent at a volume ratio of less than 3:7.In certain embodiments, the recrystallization solvent comprises waterand organic solvent at a volume ratio of less than 1:4. In certainembodiments, recrystallization solvent comprises water and organicsolvent at a volume ratio of less than 1:3, less than 1:4, less than1:5, less than 1:6, less than 1:7, less than 1:8, or less than 1:9 byvolume. In certain embodiments, the ratio is about 1:9. In any of theseembodiments, the organic solvent may comprise one or more C₁-C₈, orC₁-C₆, or C₁-C₄ alcohols. In some embodiments, the organic solventcomprises ethanol and n-propanol. In certain embodiments, the organicsolvent comprises isopropanol. In certain embodiments, the organicsolvent is isopropanol. In some embodiments, using a recrystallizationsolvent comprising water and organic solvent at a volume ratio of lessthan 3:7 by volume (such as less than 1:4, for example about 1:9)produces a crystalline form of Compound 1 with a higher yield than usinga higher ratio of water to organic solvent (such as isopropanol). Incertain embodiments, the recrystallization mixture is filtered prior tostirring until a recrystallized precipitate is formed. In someembodiments, the recrystallized precipitate is isolated bycentrifugation, filtration, or other means to form an isolatedprecipitate.

In some embodiments, when recrystallizing at least a portion of theisolated precipitate, the recrystallization mixture is stirred at atemperature of less than 50° C. In some embodiments, therecrystallization mixture is stirred at a temperature of 45° C. or less,40° C. or less, 35° C. or less, 30° C. or less, 25° C. or less, or 20°C. or less. In certain embodiments, the recrystallization mixture isstirred at a temperature between 20° C. to 45° C., between 20° C. to 40°C., between 20° C. to 35° C., between 25° C. to 45° C., between 25° C.to 40° C., or between 25° C. to 35° C. In some embodiments, therecrystallization mixture is stirred at a temperature of 30° C. or less.In certain embodiments, recrystallizing at least a portion of theisolated precipitate at a temperature of less than 50° C. (such as, forexample, between 20° C. to 40° C., or between 25° C. to 35° C., or about30° C.) produces a crystalline form of Compound 1 with a higher yieldthan using a higher recrystallization temperature.

In certain embodiments, recrystallizing at least a portion of theisolated precipitate at a temperature of less than 50° C. (such as, forexample, between 20° C. to 40° C., or between 25° C. to 35° C., or about30° C.), and using a recrystallization solvent comprising water andorganic solvent at a volume ratio of less than 3:7 by volume (such asless than 1:4, for example about 1:9) produces a crystalline form ofCompound 1 with a higher yield than using a higher recrystallizationtemperature or a higher ratio of water to organic solvent. In someembodiments, using isopropanol as the organic solvent inrecrystallization also contributes to a higher yield, compared to usinga different organic solvent in the same process.

Thus, in some embodiments, the method of making Compound 1 (such asmethods of making a bulk composition comprising Compound 1) comprisescombining the free base (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester with organic solvent to form amixture; adjusting the pH of the mixture to between 3.5 and 4.5 by theaddition of hydrochloric acid; stirring the mixture until a precipitateis formed; isolating the precipitate; dissolving at least a portion ofthe isolated precipitate in a recrystallization solvent to form arecrystallization mixture; stirring the recrystallization mixture untila recrystallized precipitate is formed; isolating the recrystallizedprecipitate to form an isolated precipitate; and drying the isolatedprecipitate under reduced pressure to produce the trihydrate form of(3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt (Compound1).

b. Wash Step

In other embodiments, at least a portion of the isolated precipitate iswashed one or more times prior to being dried under reduced pressure. Insome embodiments, at least a portion of the isolated precipitate iswashed one or more times with an aqueous wash prior to being dried underreduced pressure. In some embodiments, the isolated precipitate beingwashed one or more times was isolated from a recrystallization mixture.In other embodiments, the isolated precipitate being washed one or moretimes has not been recrystallized. In certain embodiments, the aqueouswash comprises organic solvent. In some embodiments, the organic solventcomprises one or more alcohols. In some embodiments, the organic solventcomprises one or more C₁-C₈, or C₁-C₆, or C₁-C₄ alcohols. In certainembodiments, the organic solvent comprises isopropanol, n-propanol,ethanol, or methanol, or any combinations thereof. In some embodiments,the organic solvent comprises ethanol and n-propanol. In still furtherembodiments, the organic solvent comprises isopropanol. In someembodiments, at least a portion of the isolated precipitate is washedone or more times with an aqueous wash prior to being dried underreduced pressure, wherein the aqueous wash comprises organic solvent andwater. In some embodiments, the aqueous wash comprises water and one ormore alcohols, for example water and isopropanol, n-propanol, ethanol,or methanol, or any combinations thereof. In some embodiments, theaqueous wash comprises water at about 5% to about 15% by weight, orabout 8% to about 12% by weight. In some embodiments, the aqueous washcomprises water and organic solvent at a volume ratio of less than 3:7,or less than 1:4, such as about 1:9. In some embodiments, the isolatedprecipitate is washed one or more times with an aqueous wash solutioncomprising isopropanol and water prior to being dried under reducedpressure to produce Compound 1. Thus, in some embodiments, the method ofmaking Compound 1 (such as methods of making a bulk compositioncomprising Compound 1) comprises combining the free base (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester with organic solvent to form amixture; adjusting the pH of the mixture to between 3.5 and 4.5 by theaddition of hydrochloric acid; stirring the mixture until a precipitateis formed; isolating the precipitate; washing the isolated precipitate;and, after washing, drying the isolated precipitate under reducedpressure to produce the trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt (Compound1). In some embodiments, the isolated precipitate is washed with anaqueous wash, wherein the aqueous wash comprises organic solvent andabout 5% to 15% by weight water.

In some embodiments, the temperatures or solvents (including ratios orpercentages of organic solvent and water), or ranges thereof, orcombinations of any of the forgoing, as described herein for washing theisolated precipitate, or for recrystallization, or a combinationthereof, may be combined with, for example, any of the quantities ofprecipitate or isolated precipitate or free base or Compound 1 used inthe described process; or any of the temperatures or pressures or times,or ranges thereof, or combinations of any of these, in the drying stepdescribed herein; or any of the other conditions or steps describedherein. In some embodiments, including one or more recrystallization orwashing steps as described herein, or combinations thereof, in theprocess of making a bulk composition as described herein, results in abulk composition comprising Compound 1 that has a particular stability,or organic solvent content, or water content, or ratio of trihydrate toanhydrous form, or XRPD spectra, or various combinations of these, asdescribed herein.

The provided description sets forth numerous exemplary configurations,methods, parameters, and the like. It should be recognized, however,that such description is not intended as a limitation on the scope ofthe present disclosure, but is instead provided as a description ofexemplary embodiments.

ENUMERATED EMBODIMENTS

Embodiment I-1. A bulk composition comprising a trihydrate form of (3S,4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, which hasthe following formula:

-   -   and at least one container.

Embodiment I-2. The bulk composition of embodiment I-1, comprising atleast 75% by weight of the trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, whereinthe weight excludes the weight of the at least one container.

Embodiment I-3. The bulk composition of embodiment I-1 or I-2, furthercomprising an anhydrous form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, whereinthe ratio of the trihydrate form to the anhydrous form is at least about4 to 1.

Embodiment I-4. The bulk composition of embodiment I-1 or I-2,comprising at least about 6.5% by weight water relative to the totalweight of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt present inanhydrous or trihydrate form.

Embodiment I-5. The bulk composition of embodiment I-3, wherein theratio of the trihydrate form to the anhydrous form is at least about 11to 1.

Embodiment I-6. The bulk composition of any one of embodiments I-1 toI-4, comprising at least about 7.5% by weight water relative to thetotal weight of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt present inanhydrous or trihydrate form.

Embodiment I-7. The bulk composition of any one of embodiments I-1 toI-6, wherein the trihydrate form is in a crystalline form, and whereinthe crystalline form has XRPD peaks at 7.74±0.5° and 20.95±0.5°.

Embodiment I-8. A pharmaceutical composition comprising a trihydrateform of (3S, 4R, 3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, which hasthe following formula:

-   -   and a pharmaceutically acceptable excipient.

Embodiment I-9. The pharmaceutical composition of embodiment I-8,further comprising an anhydrous form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, whereinthe ratio of the trihydrate form to the anhydrous form is at least about4 to 1.

Embodiment I-10. The pharmaceutical composition of embodiment I-8,comprising between about 6.5% to about 10% by weight water relative tothe total weight of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt present inanhydrous or trihydrate form.

Embodiment I-11. The pharmaceutical composition of embodiment I-9,wherein the ratio of the trihydrate form to the anhydrous form is atleast about 11 to 1.

Embodiment I-13. The pharmaceutical composition of any one ofembodiments I-8 to I-11, comprising between about 7.5% to about 9% byweight water relative to the total weight of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt present inanhydrous or trihydrate form.

Embodiment I-14. The pharmaceutical composition of any one ofembodiments I-8 to I-13, comprising less than 1% by weight of theanhydrous form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

Embodiment I-15. The pharmaceutical composition of any one ofembodiments I-8 to I-14, wherein the trihydrate form is in a crystallineform, and wherein the crystalline form has XRPD peaks at 7.74±0.5° and20.95±0.5°.

Embodiment I-16. A dosage form comprising the pharmaceutical compositionof any one of embodiments I-8 to I-15.

Embodiment I-17. The dosage form of embodiment I-16, wherein the dosageform comprises one or more tablets or one or more capsules.

Embodiment I-18. A kit comprising the dosage form of embodiment I-16 orI-17 and packaging.

Embodiment I-19. The kit of embodiment I-18, wherein the packaging is ablister pack.

Embodiment I-20. A method of improving gastrointestinal motility in asubject in need thereof, comprising administering to the subject in needthereof a therapeutically effective amount of the pharmaceuticalcomposition of any one of embodiments I-8 to I-15, or the dosage form ofembodiments I-16 or I-17.

Embodiment I-21. The method of embodiment I-20, wherein the subject inneed thereof has a gastrointestinal disorder.

Embodiment I-22. A method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof a therapeutically effective amount of the pharmaceuticalcomposition of any one of embodiments I-8 to I-15, or the dosage form ofembodiment I-16 or I-17.

Embodiment I-23. The method of embodiment I-21 or I-22, wherein thegastrointestinal disorder is selected from the group consisting ofgastroesophageal reflux disease (GERD), functional dyspepsia orfunctional motility disorder, gastroparesis, paralytic ileus,post-operative ileus, emesis, nausea, heartburn, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis.

Embodiment I-24. The use of embodiment I-23, wherein the GERD is protonpump inhibitor (PPI) resistant GERD.

Embodiment I-25. The use of embodiment I-23, wherein the constipation isopiate induced constipation (OIC), chronic idiopathic constipation(CIC), or constipation associated with irritable bowel syndromeconstipation type (IBSc).

Embodiment I-26. The use of embodiment I-23, wherein the esophagitis iserosive esophagitis (EE) or eosinophilic esophagitis (EoE).

Embodiment I-27. The use of embodiment I-23, wherein the IBS isirritable bowel syndrome constipation type (IBSc).

Embodiment I-28. The use of embodiment I-23, wherein the gastroparesisis diabetic gastroparesis, or idiopathic or functional gastroparesis.

Embodiment I-29. The use of embodiment I-21 or I-22, wherein thegastrointestinal disorder is selected from the group consisting ofproton pump inhibitor (PPI) resistant GERD, emesis, gastroparesis,opiate induced constipation (OIC), chronic idiopathic constipation(CIC), erosive esophagitis (EE), eosinophilic esophagitis (EoE),functional dyspepsia (FD) or functional motility disorder (FMD),intestinal pseudo-obstruction, irritable bowel syndrome constipationtype (IBSc), enteral feeding intolerance (EFI), and post-operativeileus.

Embodiment I-30. The use of embodiment I-21 or I-22, wherein thegastrointestinal disorder is selected from the group consisting ofpost-operative ileus, chronic grass sickness, constipation, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect.

Embodiment I-31. The use of embodiment I-30, wherein the gastritis isatrophic gastritis.

Embodiment I-32. Use of a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt in themanufacture of a medicament for improving gastrointestinal motility in asubject in need thereof.

Embodiment I-33. The use of embodiment I-32, wherein the subject in needthereof has a gastrointestinal disorder.

Embodiment I-34. Use of a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt in themanufacture of a medicament for treating a gastrointestinal disorder ina subject in need thereof.

Embodiment I-35. The use of embodiment I-33 or I-34, wherein thegastrointestinal disorder is selected from the group consisting ofgastroesophageal reflux disease (GERD), functional dyspepsia orfunctional motility disorder, gastroparesis, paralytic ileus,post-operative ileus, emesis, nausea, heartburn, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis.

Embodiment I-36. The use of embodiment I-35, wherein the GERD is protonpump inhibitor (PPI) resistant GERD.

Embodiment I-37. The use of embodiment I-35, wherein the constipation isopiate induced constipation (OIC), chronic idiopathic constipation(CIC), or constipation associated with irritable bowel syndromeconstipation type (IBSc).

Embodiment I-38. The use of embodiment I-35, wherein the esophagitis iserosive esophagitis (EE) or eosinophilic esophagitis (EoE).

Embodiment I-39. The use of embodiment I-35, wherein the IBS isirritable bowel syndrome constipation type (IBSc).

Embodiment I-40. The use of embodiment wherein the gastroparesis isdiabetic gastroparesis, or idiopathic or functional gastroparesis.

Embodiment I-41. The use of embodiment I-33 or I-34, wherein thegastrointestinal disorder is selected from the group consisting ofproton pump inhibitor (PPI) resistant GERD, emesis, gastroparesis,opiate induced constipation (OIC), chronic idiopathic constipation(CIC), erosive esophagitis (EE), eosinophilic esophagitis (EoE),functional dyspepsia (FD) or functional motility disorder (FMD),intestinal pseudo-obstruction, irritable bowel syndrome constipationtype (IBSc), enteral feeding intolerance (EFI), and post-operativeileus.

Embodiment I-42. The use of embodiment I-33 or I-34, wherein thegastrointestinal disorder is selected from the group consisting ofpost-operative ileus, chronic grass sickness, constipation, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect.

Embodiment I-43. The use of embodiment I-42, wherein the gastritis isatrophic gastritis.

Embodiment I-44. A compound for use in improving gastrointestinalmotility in a subject in need thereof, wherein the compound is atrihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

Embodiment I-45. The compound for use of embodiment I-44, wherein thesubject in need thereof has a gastrointestinal disorder.

Embodiment I-46. A compound for use in treating a gastrointestinaldisorder in a subject in need thereof, wherein the compound is atrihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

Embodiment I-47. The compound for use of embodiment I-45 or I-46,wherein the gastrointestinal disorder is selected from the groupconsisting of gastroesophageal reflux disease (GERD), functionaldyspepsia or functional motility disorder, gastroparesis, paralyticileus, post-operative ileus, emesis, nausea, heartburn, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis.

Embodiment I-48. The compound for use of embodiment I-47, wherein theGERD is proton pump inhibitor (PPI) resistant GERD.

Embodiment I-49. The compound for use of embodiment I-47, wherein theconstipation is opiate induced constipation (OIC), chronic idiopathicconstipation (CIC), or constipation associated with irritable bowelsyndrome constipation type (IBSc).

Embodiment I-50. The compound for use of embodiment I-47, wherein theesophagitis is erosive esophagitis (EE) or eosinophilic esophagitis(EoE).

Embodiment I-51. The compound for use of embodiment I-47, wherein theIBS is irritable bowel syndrome constipation type (IBSc).

Embodiment I-52. The compound for use of embodiment I-47, wherein thegastroparesis is diabetic gastroparesis, or idiopathic or functionalgastroparesis.

Embodiment I-53. The compound for use of embodiment I-45 or I-46,wherein the gastrointestinal disorder is selected from the groupconsisting of proton pump inhibitor (PPI) resistant GERD, emesis,gastroparesis, opiate induced constipation (OIC), chronic idiopathicconstipation (CIC), erosive esophagitis (EE), eosinophilic esophagitis(EoE), functional dyspepsia (FD) or functional motility disorder (FMD),intestinal pseudo-obstruction, irritable bowel syndrome constipationtype (IBSc), enteral feeding intolerance (EFI), and post-operativeileus.

Embodiment I-54. The compound for use of embodiment I-45 or I-46,wherein the gastrointestinal disorder is selected from the groupconsisting of post-operative ileus, chronic grass sickness,constipation, megacolon, gastritis, gastrointestinal stasis, andabomasal emptying defect.

Embodiment I-55. The compound for use of embodiment I-54, wherein thegastritis is atrophic gastritis.

Embodiment I-56. A pharmaceutical composition for use in improvinggastrointestinal motility in a subject in need thereof, wherein thepharmaceutical composition comprises a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

Embodiment I-57. The pharmaceutical composition for use of embodimentI-56, wherein the subject in need thereof has a gastrointestinaldisorder.

Embodiment I-58. A pharmaceutical composition for use in treating agastrointestinal disorder in a subject in need thereof, wherein thepharmaceutical composition comprises a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

Embodiment I-59. The pharmaceutical composition for use of embodimentI-57 or I-58, wherein the gastrointestinal disorder is selected from thegroup consisting of gastroesophageal reflux disease (GERD), functionaldyspepsia or functional motility disorder, gastroparesis, paralyticileus, post-operative ileus, emesis, nausea, heartburn, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis.

Embodiment I-60. The pharmaceutical composition for use of embodimentI-59, wherein the GERD is proton pump inhibitor (PPI) resistant GERD.

Embodiment I-61. The pharmaceutical composition for use of embodimentI-59, wherein the constipation is opiate induced constipation (OIC),chronic idiopathic constipation (CIC), or constipation associated withirritable bowel syndrome constipation type (IBSc).

Embodiment I-62. The pharmaceutical composition for use of embodimentI-59, wherein the esophagitis is erosive esophagitis (EE) oreosinophilic esophagitis (EoE).

Embodiment I-63. The pharmaceutical composition for use of embodimentI-59, wherein the IBS is irritable bowel syndrome constipation type(IBSc).

Embodiment I-64. The pharmaceutical composition for use of embodimentI-59, wherein the gastroparesis is diabetic gastroparesis, or idiopathicor functional gastroparesis.

Embodiment I-65. The pharmaceutical composition for use of embodimentI-57 or I-58, wherein the gastrointestinal disorder is selected from thegroup consisting of proton pump inhibitor (PPI) resistant GERD, emesis,gastroparesis, opiate induced constipation (OIC), chronic idiopathicconstipation (CIC), erosive esophagitis (EE), eosinophilic esophagitis(EoE), functional dyspepsia (FD) or functional motility disorder (FMD),intestinal pseudo-obstruction, irritable bowel syndrome constipationtype (IBSc), enteral feeding intolerance (EFI), and post-operativeileus.

Embodiment I-66. The pharmaceutical composition for use of embodimentI-57 or I-58, wherein the gastrointestinal disorder is selected from thegroup consisting of post-operative ileus, chronic grass sickness,constipation, megacolon, gastritis, gastrointestinal stasis, andabomasal emptying defect.

Embodiment I-67. The pharmaceutical composition for use of embodimentI-66, wherein the gastritis is atrophic gastritis.

Embodiment I-68. The method of any one of embodiments I-20 to I-27, theuse of any one of embodiments I-32 to I-41, the compound for use of anyone of embodiments I-44 to I-53, or the pharmaceutical composition foruse of any one of embodiments I-56 to I-65, wherein the subject in needthereof is a human.

Embodiment I-69. The method of any one of embodiments I-20 to I-22 orI-27 to I-29, the use of any one of embodiments I-32 to I-34 or I-41 toI-43, the compound for use of any one of embodiments I-44 to I-46 orI-53 to I-55, or the pharmaceutical composition for use of any one ofembodiments I-56 to I-58 or I-65 to I-67, wherein the subject in needthereof is a non-human animal.

Embodiment I-70. The method, use, compound for use, or pharmaceuticalcomposition for use of embodiment I-69, wherein the non-human animal isa ruminant, an equine, a cat, a dog, a rabbit, or a guinea pig.

Embodiment I-71. The method, use, compound for use, or pharmaceuticalcomposition for use of embodiment I-70, wherein the ruminant is a sheep,cow, yak, bison, or buffalo.

Embodiment I-72. The method, use, compound for use, or pharmaceuticalcomposition for use of embodiment I-70, wherein the equine is a horse ora donkey.

Embodiment I-73. The method of any one of embodiments I-20 to I-29 orI-68 to I-72, the use of any one of embodiments I-32 to I-43 or I-68 toI-72, the compound for use of any one of embodiments I-44 to I-55 orI-68 to I-72, or the pharmaceutical composition for use of any one ofembodiments I-56 to I-72, wherein the subject in need thereof is anewborn.

Embodiment I-74. The method of any one of embodiments I-20 to I-29 orI-68 to I-73; the use of any one of embodiments I-32 to I-43 or I-68 toI-73; the compound for use of any one of embodiments I-44 to I-55 orI-68 to I-73; or the pharmaceutical composition for use of any one ofembodiments I-56 to I-67 or I-68 to I-73, wherein the pharmaceuticalcomposition is administered parenterally.

Embodiment I-75. The method of any one of embodiments I-20 to I-29 orI-68 to I-73; the use of any one of embodiments I-32 to I-43 or I-68 toI-73; the compound for use of any one of embodiments I-44 to I-55 orI-68 to I-73; or the pharmaceutical composition for use of any one ofembodiments I-56 to I-67 or I-68 to I-73, wherein the pharmaceuticalcomposition is administered orally.

Embodiment I-76. The method of any one of embodiments I-20 to I-29 orI-68 to I-73; the use of any one of embodiments I-32 to I-43 or I-68 toI-73; the compound for use of any one of embodiments I-44 to I-55 orI-68 to I-73; or the pharmaceutical composition for use of any one ofembodiments I-56 to I-67 or I-68 to I-73, wherein the pharmaceuticalcomposition is administered through a gastric tube.

Embodiment I-77. The method of any one of embodiments I-20 to I-31 orI-68 to I-76; the use of any one of embodiments I-32 to I-43 or I-68 toI-76; the compound for use of any one of embodiments I-44 to I-55 orI-68 to I-76; or the pharmaceutical composition for use of any one ofembodiments I-56 to I-67 or I-68 to I-76, wherein the trihydrate form isin a crystalline form, and wherein the crystalline form has XRPD 2-theta(2θ) peaks at 7.74±0.5° and 20.95±0.5°.

Embodiment I-78. The bulk composition of any one of embodiments I-1 toI-7; or the pharmaceutical composition of any one of embodiments I-8 toI-15; or the dosage form of embodiment I-16 or I-17; or the kit ofembodiment I-18 or I-19; or the method of any one of embodiments I-20 toI-31 or I-68 to I-77; or the use of any one of embodiments I-32 to I-43or I-68 to I-77; or the compound for use of any one of embodiments I-44to I-55 or I-68 to I-77; or the pharmaceutical composition for use ofany one of embodiments I-56 to I-67 or I-68 to I-77, wherein thetrihydrate form is in a crystalline form, and wherein the crystallineform has a greater than 50% relative intensity XRPD 2-theta (2θ) peak at7.74°±0.5°, and a 100% relative intensity XRPD 2-theta (2θ) peak at20.95°±0.5°.

Embodiment I-79. The bulk composition of any one of embodiments I-1 toI-7 or I-78; or the pharmaceutical composition of any one of embodimentsI-8 to I-15 or I-78; or the dosage form of embodiment I-16 or I-17 orI-78; or the kit of embodiment I-18 or I-19 or I-78; or the method ofany one of embodiments I-20 to I-31 or I-68 to I-78; or the use of anyone of embodiments I-32 to I-43 or I-68 to I-78; or the compound for useof any one of embodiments I-44 to I-55 or I-68 to I-78; or thepharmaceutical composition for use of any one of embodiments I-56 toI-67 or I-68 to I-78, wherein the trihydrate form is in a crystallineform, and wherein the crystalline form has two or more XRPD 2-theta (2θ)peaks selected from the group consisting of 10.3°±0.2°, 13.6°±0.2°,14.8°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°,19.2°±0.2°, 21.3°±0.2°, 22.0°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°,26.0°±0.2°, 27.2°±0.2°, 30.1°±0.2°, 32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°,and 39.4°±0.2°.

Embodiment I-80. The bulk composition of any one of embodiments I-1 toI-7, I-78, or I-79; or the pharmaceutical composition of any one ofembodiments I-8 to I-15, I-78, or I-79; or the dosage form of embodimentI-16 or I-17, I-78, or I-79; or the kit of embodiment I-18 or I-19,I-78, or I-79; or the method of any one of embodiments I-20 to I-31 orI-68 to I-79; or the use of any one of embodiments I-32 to I-43 or I-68to I-79; or the compound for use of any one of embodiments I-44 to I-55or I-68 to I-79; or the pharmaceutical composition for use of any one ofembodiments I-56 to I-67 or I-68 to I-79, wherein the trihydrate form isin a crystalline form, and wherein the crystalline form has XRPD 2-theta(2θ) peaks at 7.6°±0.2° and 20.7°±0.2°.

Embodiment I-81. The bulk composition, pharmaceutical composition,dosage form, kit, method, use, compound for use, or pharmaceuticalcomposition for use of embodiment I-80, wherein the 7.6°±0.2° XRPD2-theta (2θ) peak has greater than 50% relative intensity, and the20.7°±0.2° XRPD 2-theta (2θ) peak has 100% relative intensity.

Embodiment I-82. The bulk composition, pharmaceutical composition,dosage form, kit, method, use, compound for use, or pharmaceuticalcomposition for use of embodiment I-80 or I-81, wherein the crystallineform further has two or more XRPD 2-theta (2θ) peaks selected from thegroup consisting of 10.3°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.0°±0.2°,15.4°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.3°±0.2°,22.0°±0.2° 23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 27.2°±0.2°,30.1°±0.2°, 32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°, and 39.4°±0.2°.

Embodiment I-83. The bulk composition of any one of embodiments I-1 toI-7, or I-78 to I-82; or the pharmaceutical composition of any one ofembodiments I-8 to I-15, or I-78 to I-82; or the dosage form ofembodiment I-16 or I-17, or I-78 to I-82; or the kit of embodiment I-18or I-19, or I-78 to I-82; method of any one of embodiments I-20 to I-31or I-68 to I-82; or the use of any one of embodiments I-32 to I-43 orI-68 to I-82; or the compound for use of any one of embodiments I-44 toI-55 or I-68 to I-82; or the pharmaceutical composition for use of anyone of embodiments I-56 to I-67 or I-68 to I-82, wherein the bulkcomposition, pharmaceutical composition, dosage form, kit, or medicamentcomprises less than about 6000 ppm organic solvent.

Embodiment I-83. The bulk composition, or the pharmaceuticalcomposition, or the dosage form, or the kit, or the method, or thecompound for use, or the pharmaceutical composition for use ofembodiment I-83, wherein the bulk composition, pharmaceuticalcomposition, dosage form, kit, or medicament comprises less than about5000 ppm, less than about 4000 ppm, less than about 3000 ppm, or lessthan about 2000 ppm organic solvent.

Embodiment I-84. The bulk composition, or the pharmaceuticalcomposition, or the dosage form, or the kit, or the method, or thecompound for use, or the pharmaceutical composition for use ofembodiment I-82 or I-83, wherein the organic solvent comprises one ormore C₁-C₈ alcohols.

Embodiment I-85. The bulk composition, or the pharmaceuticalcomposition, or the dosage form, or the kit, or the method, or thecompound for use, or the pharmaceutical composition for use of any oneof embodiments I-82 to I-84, wherein the organic solvent comprisesethanol, n-propanol, or isopropanol, or a combination thereof.

Embodiment I-86. The bulk composition, or the pharmaceuticalcomposition, or the dosage form, or the kit, or the method, or thecompound for use, or the pharmaceutical composition for use of any oneof embodiments I-82 to I-85, wherein the organic solvent comprisesisopropanol.

Embodiment II-1. A method of making a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, which hasthe following formula:

the method comprising:

-   -   (a) combining free base (3S, 4R,        3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic        acid 1-azabicyclo [2.2.2]oct-3′-yl ester with organic solvent to        form a mixture;    -   (b) adjusting the pH of the mixture to between 3.5 and 4.5 by        the addition of hydrochloric acid;    -   (c) stifling the mixture until a precipitate is formed;    -   (d) isolating the precipitate to form an isolated precipitate;        and    -   (e) drying the isolated precipitate under reduced pressure until        a water content of between 6.5% by weight to 10% by weight is        reached to produce the trihydrate form of (3S, 4R,        3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic        acid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

Embodiment II-2. The method of Embodiment II-1, wherein the isolatedprecipitate is dried under reduced pressure until the organic solventcontent is less than about 6000 ppm.

Embodiment II-3. The method of Embodiment II-1 or II-2, wherein theorganic solvent comprises one or more alcohols.

Embodiment II-4. The method of any one of Embodiments II-1 to II-3,wherein the organic solvent comprises ethanol, n-propanol, orisopropanol, or a combination thereof.

Embodiment II-5. The method of any one of Embodiments II-1 to II-4,wherein the organic solvent comprises isopropanol.

Embodiment II-6. The method of any one of Embodiments II-1 to II-5,wherein the free base is combined with water and organic solvent to formthe mixture.

Embodiment II-7. The method of any one of Embodiments II-1 to II-6,wherein the free base is combined with water and organic solvent to formthe mixture, wherein the water is present in the mixture at about 5% toabout 15% by weight relative to the organic solvent.

Embodiment II-8. The method of any one of Embodiments II-1 to II-7,wherein the organic solvent combined with the free base comprises one ormore alcohols.

Embodiment II-9. The method of any one of Embodiments II-1 to II-8,wherein the organic solvent combined with the free base comprises one ormore C₁-C₈ alcohols.

Embodiment II-10. The method of any one of Embodiments II-1 to II-9,wherein the organic solvent combined with the free base comprisesisopropanol.

Embodiment II-11. The method of any one of Embodiments II-1 to II-10,wherein the isolated precipitate is dried under reduced pressure at atemperature between about 20° C. to about 60° C.

Embodiment II-12. The method of any one of Embodiments II-1 to II-11,wherein the isolated precipitate is dried under reduced pressure forbetween about 3 hours to about 12 hours.

Embodiment II-13. The method of any one of Embodiments II-1 to II-12,wherein the isolated precipitate is dried under reduced pressure at atemperature between about 25° C. to about 35° C., then at a temperaturebetween about 30° C. to about 45° C., then at a temperature betweenabout 30° C. to about 50° C., and then at a temperature between about30° C. to about 55° C.

Embodiment II-14. The method of any one of Embodiments II-1 to II-13,wherein the isolated precipitate is dried under reduced pressure at atemperature between about 25° C. to about 35° C., then at a temperaturebetween about 35° C. to about 45° C., then at a temperature betweenabout 40° C. to about 50° C., and then at a temperature between about45° C. to about 55° C.

Embodiment II-15. The method of any one of Embodiments II-1 to II-14,wherein the isolated precipitate is dried under reduced pressure at atemperature between about 25° C. to about 35° C. for about 0.5 to about2.5 hours; then at a temperature between about 35° C. to about 45° C.for about 0.5 to about 2.5 hours; then at a temperature between about40° C. to about 50° C. for about 0.5 to about 2.5 hours; and then at atemperature between about 45° C. to about 55° C.

Embodiment II-16. The method of any one of Embodiments II-1 to II-15,wherein the isolated precipitate is dried under reduced pressure until awater content of between 7.5% by weight to 9.0% by weight is reached toproduce the trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt.

Embodiment II-17. The method of any one of Embodiments II-1 to II-16,wherein the reduced pressure is from about 20 mm Hg to about 60 mm Hg.

Embodiment II-18. The method of any one of Embodiments II-1 to II-17,wherein the reduced pressure is from about 30 mm Hg to about 55 mm Hg.

Embodiment II-19. The method of any one of Embodiments II-1 to II-18,wherein the trihydrate form is in a crystalline form, and wherein thecrystalline form has XRPD peaks at 7.74±0.5° and 20.95±0.5°.

Embodiment II-20. The method of any one of Embodiments II-1 to II-19,wherein at least 100 kg of the free base is combined with the organicsolvent to form the mixture.

Embodiment II-21. The method of any one of Embodiments II-1 to II-20,wherein at least 100 kg of precipitate is isolated.

Embodiment II-22. The method of any one of Embodiments II-1 to II-21,wherein at least 100 kg of isolated precipitate is dried.

Embodiment II-23. The method of any one of Embodiments II-1 to II-22,wherein at least 100 kg of the trihydrate form is produced.

Embodiment II-24. The method of any one of Embodiments II-1 to II-23,wherein at least 200 kg of the free base is combined with the organicsolvent to form the mixture.

Embodiment II-25. The method of any one of Embodiments II-1 to II-24,wherein at least 200 kg of precipitate is isolated.

Embodiment II-26. The method of any one of Embodiments II-1 to II-25,wherein at least 200 kg of isolated precipitate is dried.

Embodiment II-27. The method of any one of Embodiments II-1 to II-26,wherein at least 200 kg of the trihydrate form is produced.

Embodiment II-28. The method of any one of Embodiments II-1 to II-27,wherein after step (b) and prior to step (c), the mixture is adjusted tocomprise water and isopropanol at a volume ratio of less than 3:7.

Embodiment II-29. The method of any one of Embodiments II-1 to II-28,wherein after step (b) and prior to step (c), the mixture is adjusted tocomprise water and isopropanol at a volume ratio of less than 1:4.

Embodiment II-30. The method of any one of Embodiments II-1 to II-28,wherein after step (b) and prior to step (c), the mixture is adjusted tocomprise water and isopropanol, wherein the water is present at between5% to 15% by weight.

Embodiment II-31. The method of any one of Embodiments II-1 to II-30,wherein the mixture in step (c) is stirred at a temperature of 40° C. orless to form the precipitate.

Embodiment II-32. The method of any one of Embodiments II-1 to II-31,wherein the mixture in step (c) is stirred at a temperature of 30° C. orless to form the precipitate.

Embodiment II-33. The method of any one of Embodiments II-1 to II-32,wherein after step (d) and before step (e), at least a portion of theisolated precipitate is dissolved in a recrystallization solvent to forma recrystallization mixture, the recrystallization mixture is stirreduntil a recrystallized precipitate is formed, and the recrystallizedprecipitate is isolated to form an isolated precipitate.

Embodiment II-34. The method of Embodiment II-33, wherein therecrystallization mixture comprises water and isopropanol at a volumeratio of less than 3:7.

Embodiment II-35. The method of Embodiment II-33, wherein therecrystallization mixture comprises water and isopropanol at a volumeratio of less than 1:4.

Embodiment II-36. The method of Embodiment II-33, wherein therecrystallization mixture comprises water at 5% to 10% by weight.

Embodiment II-37. The method of Embodiment II-33, wherein therecrystallization mixture comprises isopropanol and water, wherein thewater is present at 5% to 10% by weight.

Embodiment II-38. The method of any one of Embodiments II-33 or II-37,wherein the recrystallization mixture is stirred at a temperature of 40°C. or less to form the recrystallization precipitate.

Embodiment II-39. The method of any one of Embodiments II-33 or II-37,wherein the recrystallization mixture is stirred at a temperature of 30°C. or less to form the recrystallization precipitate.

Embodiment II-40. The method of any one of Embodiments II-1 to II-39,wherein the isolated precipitate is washed prior to drying.

Embodiment II-41. The method of Embodiment II-40, wherein the isolatedprecipitate is washed with a wash solvent comprising water andisopropanol at a volume ratio of less than 3:7.

Embodiment II-42. The method of Embodiment II-40 or II-41, wherein theisolated precipitate is washed with a wash solvent comprising water andisopropanol at a volume ratio of less than 1:4.

Embodiment II-43. The method of any one of Embodiments II-1 to II-39,wherein the isolated precipitate is washed with an aqueous wash prior todrying under reduced pressure, wherein the aqueous wash comprisesorganic solvent and about 5% to about 15% by weight water.

Embodiment II-44. The method of any one of Embodiments II-1 to II-43,wherein the isolated precipitate is dried under reduced pressure untilthe organic solvent content is less than about 5000 ppm, less than about4000 ppm, less than about 3000 ppm, or less than about 2000 ppm.

Embodiment II-45. The method of Embodiment II-44, wherein the organicsolvent comprises one or more alcohols.

Embodiment II-46. The method of any one of Embodiments II-2, II-44, orII-45, wherein the organic solvent comprises one or more C₁-C₈ alcohols.

Embodiment II-47. The method of any one of Embodiments II-44 to II-46,wherein the organic solvent comprises isopropanol.

Embodiment II-48. The method of any one of Embodiments II-1 to II-47,wherein the isolated precipitate is dried under reduced pressure untilthe isopropanol content is less than about 6000 ppm.

Embodiment II-49. The method of any one of Embodiments II-1 to II-48,wherein the isolated precipitate is dried under reduced pressure untilthe isopropanol content is less than about 5000 ppm, less than about4000 ppm, less than about 3000 ppm, or less than about 2000 ppm.

Embodiment II-50. The method of any one of Embodiments II-1 to II-49,wherein the trihydrate form is in a crystalline form, and wherein thecrystalline form has a greater than 50% relative intensity XRPD 2-theta(2θ) peak at 7.74°±0.5°, and a 100% relative intensity XRPD 2-theta (2θ)peak at 20.95°±0.5°.

Embodiment II-51. The method of any one of Embodiments II-1 to II-50,wherein the trihydrate form is in a crystalline form, and wherein thecrystalline form has two or more XRPD 2-theta (2θ) peaks selected fromthe group consisting of 10.3°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.0°±0.2°,15.4°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.3°±0.2°,22.0°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 27.2°±0.2°,30.1°±0.2°, 32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°, and 39.4°±0.2°.

Embodiment II-52. The method of any one of Embodiments II-1 to II-51,wherein the trihydrate form is in a crystalline form, and wherein thecrystalline form has XRPD 2-theta (2θ) peaks at 7.6°±0.2° and20.7°±0.2°.

Embodiment II-53. The method of Embodiment II-52, wherein the 7.6°±0.2°XRPD 2-theta (2θ) peak has greater than 50% relative intensity, and the20.7°±0.2° XRPD 2-theta (2θ) peak has 100% relative intensity.

Embodiment II-54. The method of Embodiment II-52 or II-53, wherein thecrystalline form further has two or more XRPD 2-theta (2θ) peaksselected from the group consisting of 10.3°±0.2°, 13.6°±0.2°,14.8°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°,19.2°±0.2°, 21.3°±0.2°, 22.0°±0.2° 23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°,26.0°±0.2°, 27.2°±0.2°, 30.1°±0.2°, 32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°,and 39.4°±0.2°.

Embodiment II-55. A method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof a therapeutically effective amount a trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, which hasthe following formula:

Embodiment II-56. The method of Embodiment II-55, wherein thegastrointestinal disorder is selected from the group consisting ofproton pump inhibitor (PPI) resistant GERD, emesis, gastroparesis,opiate induced constipation (OIC), chronic idiopathic constipation(CIC), erosive esophagitis (EE), eosinophilic esophagitis (EoE),functional dyspepsia (FD) or functional motility disorder (FMD),intestinal pseudo-obstruction, irritable bowel syndrome constipationtype (IB Sc), enteral feeding intolerance (EFI), and post-operativeileus.

Embodiment II-57. The method of Embodiment II-55, wherein thegastrointestinal disorder is selected from the group consisting ofpost-operative ileus, chronic grass sickness, constipation, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect.

EXAMPLES

The following Examples are merely illustrative and are not meant tolimit any aspects of the present disclosure in any way.

Example 1: Synthesis of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester, dihydrochloride salt,trihydrate

A 4,000-L reactor was charged with approximately 250 kg of crude (3S,4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester in isopropyl alcohol (300 kg)and water (80 L). Then, under a nitrogen atmosphere, and stifling at 80rpm, 80 kg of 32% HCl was introduced slowly, keeping the temperature ofthe mixture below 45° C. and the pH around 4.0. When addition wascomplete, the solution temperature was cooled to 25° C. and stifling wascontinued for at least 2 hours until the product precipitated. Then, 800kg of isopropyl alcohol was charged into the reactor over a period of 2to 4 hours, and the mixture was stirred for another 90 minutes. Thecrude precipitate (283 kg) was isolated by centrifugation. The crudeproduct was purified by crystallization in the following manner: Water(100 L) was added to the crude product. Partial vacuum was applied andthen the reactor was purged with nitrogen. Agitation was set at 80 rpm,and the temperature of the aqueous mixture was brought to 55° C. Themixture was stirred at 55° C. until the solid was dissolved, then thesolution was filtered in order to remove any foreign solid matter. Tothe solution was added 330 kg of isopropyl alcohol (resulting inapproximately 100 L:420 L water:isopropanol). The temperature of thesolution was brought to 25° C. and then stirred at 80 rpm for at least 2hours until the material precipitated. The precipitate was isolated bycentrifugation.

The wet dihydrochloride salt (252 kg) was then charged into a cone dryerand the jacket temperature of the dryer set at 30° C. and vacuum(pressure=35 mmHg) was applied for 1 hour 20 minutes. The jackettemperature was then brought to 40° C., still under 35 mmHg of pressure,for 1 hour and 10 minutes. The jacket temperature was then brought to45° C. for 1 hour. Finally, the jacket temperature was brought to 50° C.until the % water in the product, as measured by Karl Fisher analysis,was 8.0 to 8.4% and the isopropanol content was below 5,000 ppm. After 2hours at 50° C., water content was 8.46% and isopropanol content was50,238 ppm. After 5 hours at 50° C., the contents were 8.40% and 1,994ppm, respectively, and drying was stopped.

Example 2: Dehydration Profile by Thermographic Analysis

Thermographic analysis (TGA) curves were generated for the anhydrate andtrihydrate using a Perkin Elmer TGA-7. Three to five milligram sampleswere weighed into aluminum sample pans and run under dry nitrogen at 5°C./minute from 25° C. to 250° C. The data were exported to Excel toenable plotting. The sample of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester, dihydrochloride salt,trihydrate, exhibited a % loss of 8.2% by 63° C., corresponding to theloss of 3 molecules of water per molecule of compound.

Representative TGA scans for the anhydrate and trihydrate are shown inFIG. 5 . The two differ in the appearance of the dehydration mass lossobserved for the trihydrate and absent as expected from the anhydrate.Dehydration of the trihydrate started immediately upon start of heatingand was complete by approximately 50° C. Complete dehydration below 100°C. is consistent with the assignment of the trihydrate as a channel typehydrate.

Example 3: Water Vapor Sorption Isotherm

A water vapor isotherm was obtained using a Surface Measurements SystemDVS-1 equilibrated to 25° C. Approximately 7 mg of the trihydratecompound was spread in a thin layer on a glass sample holder andpre-dried at 0% relative humidity before starting the run. The isothermwas then obtained by scanning the sample from 0% RH to 90% RH and backto 0% RH at a rate of 2% RH per hour. The results are shown FIG. 4 .

As shown in the figure, dehydration and rehydration occur quickly acrossa thin layer of compound. Factors influencing the rate of re-equilibriuminclude bed depth and/or sample mass, and the magnitude of humiditychange from the critical humidity. For example, increasing the bed depthfrom 1 millimeter to 7 millimeter resulted in a change of rate fordehydration or rehydration. Re-equilibrium was established withinminutes for the 1 mm layer but required hours for the 7 mm layer, when0% RH and 55% RH were used as the humidity drivers. If relativehumidities (RH) closer to the critical RH (15-20% RH) had been chosen,it is expected that the re-equilibration times would have been longerover all.

The critical relative humidity increased with increasing temperature.Minimum relative humidities required to maintain the trihydrate were:20% RH (25° C.), 25% RH (40° C.), 30% RH (50° C.), and 50% RH (60° C.).Use of very high humidities at elevated temperatures to maintain thehydrate may not be advisable as deliquescence was observed at 100% RHfor temperatures of 40° C. and above.

Example 4: X-Ray Powder Diffraction

X-ray powder diffraction (XRPD) was performed on samples of theanhydrous form and the trihydrate using a Bruker D5000 X-raydiffractometer. The D5000 was equipped with a 2.2 kW Cu anode x-raytube, an Anton Parr TTK-1 low temperature stage and high speed positionsensitive detector (PSD). Cu Kα radiation (λ=1.5418 Å) was used toobtain all powder patterns. A dual foil, nickel filter was placed in thereceiving path of the X-rays to remove the Kβ radiation. Material wasmounted and analyzed on a front loading sample holder. Scans wereperformed over the range of below 4° to 40° 2-theta (2θ), at a 0.02°step size for 0.2 and 0.5 seconds per step.

Representative XRPD patterns for the anhydrate and trihydrate forms areshown in FIG. 3 . Each form is a unique crystalline phase as is evidentby the individual diffraction patterns. The anhydrate form exhibitsmajor specific peaks at 4.55°±0.5° (>50% relative intensity), and at13.5°0±0.5°, the latter being the most intense peak (100% relativeintensity).

The trihydrate form exhibits major specific peaks at 7.74°±0.5° (>50%relative intensity), and at 20.9°5±0.5°, the latter being the mostintense peak (100% relative intensity). A more detailed peak list forthe trihydrate from XRPD analyses includes (in degrees 2-theta (2θ))approximately 7.6°±0.2°, 10.3°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.0°±0.2°,15.4°±0.2°, 17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.7°±0.2°,21.3°±0.2°, 22.0°±0.2°, 23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°,27.2°±0.2°, 30.1°±0.2°, 32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°, 39.4°±0.2°.

During dehydration and rehydration of the trihydrate, no transitionalstate was observed, rather the material exists in either one form or theother depending on the amount of water retained in each individualcrystal. During in-situ dehydration and re-hydration, both forms wereobserved in the same pattern, at varying levels.

Example 5: NMR Characterization of the Trihydrate

¹H-Nuclear Magnetic Resonance Spectroscopy (¹H-NMR): Approximately 6 mgof the trihydrate was dissolved in in 1 g of deuterated solvent(dimethylsulfoxide (DMSO)-C45 99.9% d, with 0.05% v/v tetramethylsilane(TMS)). A Varian Gemini 300 MHz FT-NMR spectrometer was used to obtainthe ¹H-NMR spectrum. A list of the peaks is provided in Table 1 below. Arepresentative ¹H-NMR spectrum is provided in FIG. 6 .

TABLE 1 ¹H-NMR peak list for trihydrate Chemical Shift (ppm) Peak TypeIntegral 10.76 broad singlet 1.14 9.44 broad singlet 0.89 8.11, 8.51Broad doublet 1.01 7.72 singlet 0.93 6.53 singlet 1.00 6.06 broadsinglet 2.00 4.97, 4.96, 4.94 broad multiplet 0.91 ~4.20-~4.10 broadmultiplet 0.96 3.86 singlet 21.53 3.79, 3.75 broad multiplet 3.69 broadpeak 3.65, 3.62, 3.60, 3.57 doublet, doublet 3.46 singlet ~3.38 broadpeak 3.34 singlet ~3.24-~3.08 overlapping multiplets ~3.08-~2.96 broadpeak 2.42, 2.39, 2.37 triplet 2.15 ~2.24-~2.18 broad multiplet 1.21~2.02-~1.64 overlapping multiplets 10.44 1.63, 1.61, 1.58, 1.56, 1.53triplet, triplet 1.35, 1.33, 1.30, 1.28, ~1.25 triplet, triplet 2.111.05, 1.03 doublet 0.13 0.00 singlet NA (TMS)

¹³C-Nuclear Magnetic Resonance Spectroscopy (¹³C-NMR): Approximately 46mg of the trihydrate was dissolved in 1 mL of deuterated solvent(deuterium oxide, Aldrich, 99.9% D, TPAS 0.75%). The ¹³C-NMR spectrumwas obtained using a Varian Gemini 300 MHz FT-NMR spectrometer. A listof the peaks is provided in Table 2 below. A representative ¹³C-NMRspectrum is provided in FIG. 7 .

TABLE 2 ¹³C-NMR peak list for trihydrate Chemical Shift (ppm) RelativePeak Height 188.305 NA (TPAS) 178.368 81 68.659 82 160.787 85 151.267 84134.247 59 113.575 88 112.604 82 101.171 55 76.757 63 70.297 77 60.32275 59.350 52 58.834 72 55.736 73 54.355 45 54.051 36 49.845 53 49.473 7648.638 79 36.241 69 28.179 67 26.965 45 26.411 70 26.168 74 25.978 6622.395 64 19.168 67 0.000 NA (TPAS)

Example 6: 12-Month Stability of the Anhydrous Form of theDihydrochloride Salt under Controlled Temperature and Humidity

The dihydrochloride salt, anhydrous form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester, was placed in stabilitychambers with temperature and humidity controlled, for up to 12 months.The temperature was set at 25° C., and the relative humidity was set at60%. The samples were assayed at time zero, then at 3, 6, 9, and 12months using an HPLC method. The HPLC conditions were as follows:

-   -   Column: Inertsil C8-3, 250 mm length, 3 mm diameter, 5 um        particle size    -   Mobile Phase A: 2000 mL water+3 mL formic acid    -   Mobile Phase B: 1000 mL methanol+3 mL formic acid    -   Flow rate: 0.6 mL/min    -   Detection wavelength: 275 nm    -   Injection volume: 20 uL    -   Time: 50 minutes

The results are shown in Table 3 below. Although the purity of thecompound remained within the specifications originally set for theactive material (Purity HPLC Area %), the strength of the activepharmaceutical ingredient (API) decreased over time due to an increasein the water content (from 0.45% at time zero to 8.47% at 6 months, andthen stable up to 12 months). This is an approximately 8% decrease instrength of the active ingredient, which puts the product out of theacceptable range of Good Manufacturing Practice (GMP) releasespecifications originally set for this material.

TABLE 3 Stability of the Anhydrate form of the Dihydrochloride Salt at25° C./60% RH Time (months) 0 3 6 9 12 Purity HPLC (Area %) 99.3 99.299.3 99.2 99.3 Water Content 0.45% 6.47% 8.47% 8.20% 8.43%

Example 7: 36-Month Stability of the Trihydrate Form of theDihydrochloride Salt under Strictly Controlled Conditions of Temperatureand Humidity

The trihydrate form of the dihydrochloride salt of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester, was placed in stabilitychambers with temperature and humidity control for up to 36 months. Thetemperature was set at 25° C., and the relative humidity was set at 60%.The samples were assayed at time zero, then at 3, 6, 9, 12, 18, 24, and36 months using an HPLC method as described in the example above. Theresults are shown in Table 4 below.

TABLE 4 Stability of the Trihydrate form of the Dihydrochloride Salt at25° C./60% RH Time (months) 0 3 6 9 12 18 24 36 Purity HPLC (Area %)99.8 100.2 100 99.9 99.1 100 99.6 99.5 Water Content 8.5% 8.6% 8.6% 8.4%8.4% 8.6% 8.6% 8.6%

The results show that the trihydrate form is stable for at least 36months with regard to both purity and strength. The water content of theAPI did not change for up to 36 months. This batch of material wouldpass GMP certification for use in humans after 36 months followingsynthesis of the API.

Example 8: Stability of the Trihydrate Form of the Dihydrochloride Saltwhen Stored in Bulk in a GMP Storage Facility

The trihydrate form was evaluated for stability with regard to purityand strength over a time period of up to 11 years, by storing it in aGMP facility under controlled conditions of temperature and relativehumidity (temperature=room temperature and relative humidity>30%).Results are presented in Table 5 below.

TABLE 5 Stability of the Trihydrate form of the Dihydrochloride Saltwhen stored in bulk at Room Temperature and RH > 30% Year Tested 20182018 2007 (Drum #1) (Drum #2) Purity HPLC (Area %) 99.6 99.6 99.6 WaterContent 8.8% 8.4% 8.7%

These results demonstrate that the trihydrate form of the API is stableunder GMP storage when stored under the temperature and humidityconditions that are usually applied in GMP storage facilities.

Example 9: Polymorph Screen

A polymorph screen was performed on the anhydrous dihydrochloride saltof (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester, by recrystallizing the materialunder approximately 90 different crystal growth conditions and analyzingthe recovered solids using X-ray powder diffraction (XRPD). A secondaryscreen was performed using noncompetitive slurry experiments followed byX-ray diffraction of the solids. From this screen, three differentsolid-state crystal forms of the anhydrous salt were identified (Form I,Form II, and Form III), and a solid-state crystal form of the trihydratewas identified (Form IV). An amorphous form was also identified.Further, it was discovered that Form I could be converted to Form IVunder certain conditions.

The crystal growth or desaturation conditions for the recrystallizationpanels are summarized in Table 6 below. Each recrystallization panelcontained 22-32 wells, with each well containing different solventcompositions. The solvent matrices used for the three panels of thepolymorph screen and the conditions of the screens are provided inTables 7, 8, and 9, which also list the resulting crystalline form ofeach crystallization experiment based on X-ray diffraction data.

TABLE 6 Summary of Solvent Recrystallization Panels. No. of SaturationGrowth Nitrogen Experiments Scale Temperature Temperature Flow RatePanel (No. of wells) (mL) (° C.) (° C.) (psig) I 22 5-10 40 40 5 II 3210 30 30 7 III 32 10 50 50 10

TABLE 7 Panel I Matrix (Saturation/Growth Temperature = 40° C.). Tophalf of panel lists solvent ratios as solvent:cosolvent. Results of thepanel are in the bottom half. Solvent Solute Volume Mass Recovered WellSolvent System (mL) (mg) Solids Form 1 methanol 5 250 white/brownamorphous 2 ethanol 10 100 tannish Form I 3 1 propanol 10 50 tannishForm IV 4 ethylene glycol 10 100 amorphous 5 water 10 150 brownishamorphous 6 MEK 10 50 tannish insol 7 methylene 10 50 insol chloride 8chloroform 10 50 tannish insol 9 acetone 10 50 insol 10 2 propanol 10 50Form I 11 1 butanol 10 50 Form I 12 DMF 10 50 tannish Form I 13 DMA 1050 yellowish 14 butyl amine 10 150 brownish gel w/needles 15 MTBE 10 50insol 16 isopropyl acetate 10 50 insol 17 nitromethane 10 50 tannishForm I 18 isopropyl ether 10 50 insol 19 EtOAc 10 25 insol 20acetonitrile 10 25 white Form I 21 toluene 10 25 insol 22 heptane 10 25insol

TABLE 8 Panel II Matrix (Saturation/Growth Temperature = 30° C.). Tophalf of panel lists solvent ratios as solvent:cosolvent. Results of thepanel are in the bottom half. Solvent 1 2 3 4 CoSolvent EtOH A 9:1 7:33:7 1:9 water MeOH B 9:1 7:3 3:7 1:9 1-propanol Water C 9:1 7:3 3:7 1:92-propanol butyl amine D 9:1 7:3 3:7 1:9 1-butanol 1-propanol E 9:1 7:33:7 1:9 ACN EtOH F 9:1 7:3 3:7 1:9 1-propanol DMF G 9:1 7:3 3:7 1:9toluene DMA H 9:1 7:3 3:7 1:9 nitromethane EtOH A Form II am am am waterMeOH B Form II Form II Form II + IV Form IV 1-propanol Water C am am amForm IV 2-propanol butyl amine D gel gel gel gel 1-butanol 1-propanol EForm IV Form II Form IV Form IV ACN EtOH F Form IV Form IV Form IV FormIV 1-propanol DMF G Form IV Form I gel insol toluene DMA H Form IV FormIV Form IV nitromethane

TABLE 9 Panel III Matrix (Saturation/Growth Temperature = 50° C.). Tophalf of panel lists solvent ratios as solvent:cosolvent. Results of thepanel are in the bottom half. Solvent 1 2 3 4 CoSolvent EtOH A 9:1 7:33:7 1:9 water MeOH B 9:1 7:3 3:7 1:9 1-propanol Water C 9:1 7:3 3:7 1:92-propanol DMF D 9:1 7:3 3:7 1:9 methanol 1-propanol E 9:1 7:3 3:7 1:9ACN EtOH F 9:1 7:3 3:7 1:9 1-propanol DMF G 9:1 7:3 3:7 1:9 toluene DMAH 9:1 7:3 3:7 1:9 nitromethane EtOH A III + am am am am water MeOH B amII II I 1-propanol Water C am am am II 2-propanol DMF D III + am II IIIIII methanol 1-propanol E I I I + am I ACN EtOH F am II + I I I1-propanol DMF G IV II insol insol toluene DMA H low sol IV I Initromethane

Noncompetitive Slurry Experiments for Polymorph Screening:Noncompetitive slurry experiments were performed as a supplementalpolymorph screening method. When suspensions of a polymorphic materialare prepared, any polymorphic form with a lower solubility (morethermodynamically stable form) can nucleate. The nucleated forms canconvert all the residual solids to the nucleated form viasolvent-mediated phase transition. Suspensions of the isolated Form Iwere prepared by adding excess solid to several different solventsystems. The suspensions were stirred vigorously at ambient temperaturefor 3 weeks. The remaining solids were collected by vacuum filtrationand analyzed by powder X-ray diffraction to determine if any changes inthe crystalline form of the solids occurred. The results of thenoncompetitive slurry work are shown in Table 10 below.

TABLE 10 Summary of Noncompetitive Slurry Experiments SolventAntisolvent Temperature Resulting Form 1-Propanol Water Ambient Form 1Ethanol Water Ambient Form 1 Methanol Water Ambient Form 1 Water WaterAmbient Form 1 Acetonitrile Water Ambient Form 1

Based on the outcome of the slurry experiments, it was determined thatForm I is the most thermodynamically stable anhydrous form.

The recrystallization data in Table 8 (Panel II) shows that thetrihydrate Form IV can be obtained by recrystallization from awater:2-propanol solvent mixture at a ratio of less than 3:7 by volume(less than 30% water and 70% isopropanol by volume) and at a temperaturenot exceeding 40° C. Certain solvents used in the experiments, such asDMA and DMF, can be difficult to remove from compositions (such as bulkcompositions) due to their high boiling point. In some situations,trying to remove these high boiling solvents from a composition requiresconditions that can be destabilizing to the desired compound, such asrequiring heating in combination with very low pressure.

1-30. (canceled)
 31. A pharmaceutical composition comprising acrystalline form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di- hydrochloride salt, whereinthe crystalline form is characterized by XRPD 2θ peaks at 7.74±0.5° and15.0±0.2, and a pharmaceutically acceptable excipient.
 32. Thepharmaceutical composition of claim 31, wherein the crystalline form isa trihydrate form of (3S, 4R,3′R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoicacid 1-azabicyclo[2.2.2]oct-3′-yl ester di-hydrochloride salt, which hasthe following formula:


33. The pharmaceutical composition of claim 31, wherein the crystallineform is further characterized by one or more XRPD 20 peaks selected fromthe group consisting of 10.3°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.4°±0.2°,17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.3°±0.2°, 22.0°±0.2°23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 27.2°±0.2°, 30.1°±0.2°,32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°, and 39.4°±0.2°.
 34. Thepharmaceutical composition of claim 31, wherein the crystalline form isfurther characterized by two or more XRPD 2θ peaks selected from thegroup consisting of 10.3°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.4°±0.2°,17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.3°±0.2°, 22.0°±0.2°23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 27.2°±0.2°, 30.1°±0.2°,32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°, and 39.4°±0.2°.
 35. Thepharmaceutical composition of claim 31, wherein the crystalline form ischaracterized by three or more XRPD 2θ peaks selected from the groupconsisting of 10.3°±0.2°, 13.6°±0.2°, 14.8°±0.2°, 15.4°±0.2°,17.5°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.3°±0.2°, 22.0°±0.2°23.6°±0.2°, 24.3°±0.2°, 25.2°±0.2°, 26.0°±0.2°, 27.2°±0.2°, 30.1°±0.2°,32.4°±0.2°, 33.4°±0.2°, 38.2°±0.2°, and 39.4°±0.2°.
 36. Thepharmaceutical composition of claim 31, wherein the crystalline form isfurther characterized by an XRPD 2θ peak at 20.95°±0.5°.
 37. Thepharmaceutical composition of claim 31, wherein the crystalline form isfurther characterized by an XRPD 2θ peak at 21.3°±0.2°.
 38. A method ofimproving gastrointestinal motility in a subject in need thereof, themethod comprising administering a therapeutically effective amount ofthe pharmaceutical composition of claim 1 to the subject.
 39. The methodof claim 38, wherein the subject in need thereof has a gastrointestinaldisorder.
 40. The method of claim 39, wherein the gastrointestinaldisorder is selected from the group consisting of gastroesophagealreflux disease (GERD), functional dyspepsia, functional motilitydisorder, gastroparesis, paralytic ileus, post-operative ileus,intestinal pseudo-obstruction, irritable bowel syndrome (IBS),constipation, enteral feeding intolerance (EFI), esophagitis, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect. 41.The method of claim 39, wherein the gastrointestinal disorder isselected from the group consisting of gastroesophageal reflux disease(GERD), functional dyspepsia, functional motility disorder,gastroparesis, paralytic ileus, post-operative ileus, emesis, intestinalpseudo-obstruction, irritable bowel syndrome (IBS), constipation,enteral feeding intolerance (EFI), and esophagitis.
 42. The method ofclaim 39, wherein the gastrointestinal disorder is selected from thegroup consisting of post-operative ileus, constipation, megacolon,gastritis, gastrointestinal stasis, and abomasal emptying defect.
 43. Amethod of treating a gastrointestinal disorder in a subject in needthereof, the method comprising administering a therapeutically effectiveamount of the pharmaceutical composition of claim 1 to the subject,wherein the gastrointestinal disorder is selected from the groupconsisting of gastroesophageal reflux disease (GERD), functionaldyspepsia, functional motility disorder, gastroparesis, paralytic ileus,post-operative ileus, intestinal pseudo-obstruction, irritable bowelsyndrome (IBS), constipation, enteral feeding intolerance (EFI),esophagitis, megacolon, gastritis, gastrointestinal stasis, and abomasalemptying defect.
 44. The method of claim 43, wherein thegastrointestinal disorder is selected from the group consisting ofgastroesophageal reflux disease (GERD), functional dyspepsia, functionalmotility disorder, gastroparesis, paralytic ileus, post-operative ileus,emesis, intestinal pseudo-obstruction, irritable bowel syndrome (IBS),constipation, enteral feeding intolerance (EFI), and esophagitis. 45.The method of claim 43, wherein the gastrointestinal disorder isselected from the group consisting of post-operative ileus,constipation, megacolon, gastritis, gastrointestinal stasis, andabomasal emptying defect.